Parenterals

Question 1

What are Parenterals?

Answer 1

Par= outside enterals= intestine
-Injections: delivery of drug through layers of the skin or mucous membranes

-Has to be sterile and pyrogen-free -> BWI are free from pyrogens

Question 2

Cons and Pros of Parenterals:

Answer 2

PROS
-alternative route
-avoids poor GI absorption (degradation, first-pass metabolism) and gut irritation
-fast onset (emergency, unconsciousness)
-can have a local effect (intra-muscular)
-long-acting drugs

Cons:
-proper technique required
-painful
-can’t be removed, once taken
-severe adverse effects
-costly and difficult to produce (HEPA filter, air pressure)

Question 3

What are the 3 intravascular routes?

Answer 3

Intravascular
Intraarterial
Intravenous

Bypasses ABSORPTION

Question 4

What is small volume parenteral SVP?

Answer 4

-usually <100 ml,
-Common: 1-30 ml

-Bolus often small volume (1 or 5 ml)
-Multiple doses: 30 ml or more

-Single-dose don’t have preservatives made with sterile WFI
-multiple-dose SVPs always have preservatives made with bacteriostatic WFI

-Packaged in vials, ampules, pre-filled syringes, dry powder forms for reconstitution

Question 5

What are the different types of Injection for SVPs?

Answer 5

-ready for injection: Solution ->Dry soluble powder (dried down through lyophilization) bc it is not stable in solution for a long time

-Injectable Suspension -> dry insoluble and unstable products, reconstituted right before injection

-injectable emulsions (f.e. anesthesia)

Question 6

What are large volume parenterals LVPs

Answer 6

-IV infusion
-for fluid replacement, electrolyte-balance restoration, or for total
parenteral nutrition (TPN)
-100 ml - 1L or more p day
-must not contain bacteriostatic agents, no preservatives needed bc a single dose (not reused)

Question 7

What are some examples of LVPs?

Answer 7

-DW5 (5% dextrose water)
-Dextrose and NaCl
-NaCl injection
-Mannitol injection (to produce more urine)
-Ringers injection (treat dehydration, with electrolytes)
-Lactated injection (treat dehydration, with electrolytes))

Question 8

How is total parenteral nutrition (TPN) applied?

Answer 8

-Base Solution (macronutrients): amino acids, dextrose, lipids as piggy-bag, total parenteral admixture (TNA), or 3in1 admixture

-Micronutrients: electrolytes, trace elements and vitamins

Question 9

What are 2in1 or 3in1 TPN?

Answer 9

-Fat has to be in a separate bag, bc emulsions have a milky appearance and can mask precipitations

-2in1: often in the hospital, 3in1 often at home when compatible and stable

Compounding:
Gravity method: just fill the bag
Underfilled bag: Dextrose is in the bag + fill amino acids to it
Dual-compartment: one compartment has dextrose and amino acids that are compatible and the other one has lipids
Automated: delivered by software with certain percentage of the ingredients

Question 10

What is an IV admixture?

Answer 10

An IV fluid with one or more added sterile products or drugs (50 mL or more)
-made in an aseptic area in a laminar hood
-admixture has to be compatible with IV fluid

Question 11

What are 2in1 or 3in1 TPN?

Answer 11

-Fat has to be in a separate bag, bc emulsions have a milky appearance and can mask precipitations

-2in1: often in the hospital, 3in1 often at home when compatible and stable

Compounding:
Gravity method: just fill the bag
Underfilled bag: Dextrose is in the bag + fill amino acids to it
Dual-compartment: one compartment has dextrose and amino acids that are compatible and the other one has lipids
Automated: delivered by software with a certain percentage of the ingredients

Question 12

What are vehicles and excipients used for parenteral?

Answer 12

-Vehicles: SWI, BWI, non-aqueous vehicles: oils or co-solvents (have to be inert and non-toxic)

-Excipients: Preservatives, buffers, solubilizers, antioxidants

Question 13

Which excipients are not allowed to be used in parenteral?

Answer 13

-some preservatives cant be used in neonatal/pediatric formulations e.g. Benzyl alcohol

-No dyes

Question 14

What is a Hermetic container?

Answer 14

Airtight container to prevent entry into the solution

-Single dose: the robber is not resealable -> Ampule, Vial, Bags
-Multiple doses: Rubber closure is resealble

Question 15

What are the materials used for parenteral containers?

Answer 15

-Glass: composed of silicon dioxide
Type 1 is borosilicate glass most resistant to hydrolytic degradation and can resist high temperature and extreme pH - often used for parenteral preparation
Type 2,3 and Nonparental glass is not as strong

-Plastic: is light and unbreakable, but adsorption (Nitroglycerin and Insiulin) on plastic, is not visible, constituents may leach into the product, and it is not impermeable to vapor

-Robber closure: should avoid coring (shedding of robber when using a syringe)

Question 16

What are the components of syringes?

What is the Gauge?

Answer 16

-Made of plastic or glass
-Plunger to push out the content, the barrel contains the content
-the needle is positioned on the Hub

Gauge: s a measure of the outside diameter of the shaft (needle) -> varies from 13-27 - the bigger the number the smaller the diameter

Question 17

What are the components of syringes?

What is the Gauge?

Answer 17

-Made of plastic or glass
-Plunger to push out the content, the barrel contains the content
-the needle is positioned on the Hub

Gauge: s a measure of the outside diameter of the shaft (needle) -> varies from 13-27 - the bigger the number the smaller the diameter

-Filter needles have little filters inside to prevent contamination when applying content from SVP to LVP (IV admixtures)

-Needles have to be disposed in sharps container

Question 18

What is the difference between a Peripheral and Venous catheter?

Answer 18

Peripheral catheter: for Blood transfusion, drawing blood, chemotherapy, short-term infusions

Venous catheter: goes into the central vein in the neck, upper chest, or groin -> more fluid delivered in larger tube for long-term infusion

Question 19

Special devices: Pre-filled Syringes

Answer 19

Prefilled syringes
-Often for biological or biotech-based drugs bc there are unstable
-easy to use and reduce risk of errors and contamination, no solution transfer needed which saves costs

Administration set: for IV fluids
-with drips, chamber, piercing pin, Y-site
-Y-site to add an additional drug, aspirate air

Piggy-bag
-to separate medication or fluids -> 2in1, 3in1
-Advantage: Incompatibilities avoided, some dilution, don’t need to venipuncture again, meds can be given in intervals

Question 20

Special devices: Infusion devices

Answer 20

-Infusion devices: Gravity IV administration sets or automatic pumps

-Patient-controlled analgesia: patient controls the degree of relief, but so designed that can’t be overdosed, often after surgery

Question 21

What are the requirements of a Production facility for parenteral?

Answer 21

▪ Special floor plan
▪ Filtered air supply
▪ UV lights
▪ Sterile equipment and work clothing
▪ Personnel access to all controlled areas through change rooms -> Personnel is the primary source of contamination

Question 22

How is the facility tested for sterility?

Answer 22

-Atmosphere: Microbes attached to dust particles, fungal spores
-> Settle plates and open Petri dish

-Solid surfaces: mostly contaminated by dust depending on roughness, charge, and chemical properties of surface
-> rub swab and incubate, contact plates with agar medium

-Personnel: skin, nose, mouth (S. aureus)
-> Finger dabs -> incubate

-Water: used for cleaning, in the pipes (E. coli)
-> high water flow rate prevents biofilm formation, USP water should have less than 100 CFU/ml

Question 23

What is a clean room design?

Answer 23

-pharmaceutical parenteral are prepared in clean rooms
-HEPA filters, LAMINAR flow
-Personnel with gloves and special clothes

Answer 24

-High-Efficiency Particulate Air Filter
-Filter out particles that are 0.3 or greater in size - stick on the filter
-particles smaller than 0.3 can be trapped in the filters

-Filters are tested with a monodisperse aerosol of dioctylphthalate (DOP), also a test for the air velocity

Question 25

What is the ISO Standards for clean rooms?
Is the HEPA ISO ready?

Answer 25

-Certain number of particles in a certain cubic meter
-the higher the class, the more particles there will be, and the more tolerance for the number of impurities

-ISO 5 - Class 100: not more than 100 particles in 3520 cubic meter

Question 26

What are precautions for the Personnel?

Answer 26

-Avoid traffic & unnecessary movements or talking
-No eating or smoking
-Communication through telephone
-Changing room, change clothes before entering the next room

Question 27

Requirements when working in a LAMINA flow?

Answer 27

-Workbench, Needle & syringe must be asepticized
-Disinfect ampuls
-avoid coring when withdrawing from vials
-Use an additive cap or seal when done
-can’t leave the workbench

Question 28

Overview of a Manufacturing Process:

Answer 28

Cleaning and Filling
-Rack loading washers
-Filling in Class 100 area
-Lyophilization for unstable products
-keep overages?
-CGMP standards

Sealing & Sterilization
-Ampuls -> tips seals
-Vials -> rubber closure
-terminal sterilization is possible

Question 29

COMPOUNDED STERILE PREPARATIONS (CSP):

Answer 29

-CATEGORY 1: must be in ISO Class 5 - short BUD
-CATEGORY 2: cleanroom suite - longer BUD
-CATEGORY 3: sterility testing, endotoxin testing, personnel qualification, - BUD of 180 days

Question 30

What is Sterilization?

Answer 30

Killing microbes and their spores
-Sterility Assurance Level (SAL): Probability of sterility
-10^-6 required: one in a million chance of contamination

Question 31

Which methods are used for sterilization?
10^-6 SAL

Answer 31

-Terminal sterilization or aseptic manufacture (working)
-Terminal methods: heat (steam or dry), radiation, microbiocidal gas

methods require SAL of 10^-6, should be safe for operator and products, have short exposure time, and not costly

Question 32

What is steam sterilization? Preparation must be stable at the temperature
TERMINAL STERILIZATION

Answer 32

-Saturated steam under pressure (remember:121 °C/15 mts) in an autoclave - the temperature can be increased for reduced time
goes inside the microbe and denatures the proteins

-can cause moisture, so only for products (surgical dressing, aqueous products, rubber, and plastics) that already has moisture, not for oily products

Question 33

What is Dry Heat Sterilization?
Preparation must be stable at the temperature
TERMINAL STERILIZATION

Answer 33

Hot oven -> 160-1700C/2 h or 250°C for 30 min, preparation should be stable at the temperature
-Dehydration followed by oxidation
-f.e. Glassware covered with aluminum foil

Question 34

How can heat-sensitive material be sterilized?
Explain Sterilization by Filtration:

Answer 34

can be used for heat-sensitive materials
-filter microorganisms with a 0.2 µm membrane filter (DONE ASEPTICLY)

Question 35

Gas and Radiation Sterilization:

Answer 35

-Gas Sterilization: exposure to ethylene oxide gas for heat-sensitive material, medical devices (costly)

-Ionizing Radiation: Gamma radiation from Cobalt-60 is typically used, for medical devices and hospital supplies (bigger equipment)

Question 36

What is the Quality Control Test:

Answer 36

-Visual: container leaks, cloudiness, particulates in solution, solution color and volume

detect particles of about 50 μm size with a light and black background
-leaker test for ampuls -> put dye in autoclave with dye bath, check if the inside of ampul changes color

Question 37

Sterility Test:

Answer 37

-direct inoculation
-membrane filtration method: incubate the filter -> there should be growth if the filter works

Question 38

Pyrogen testing:

Answer 38

-free of Endotoxins, or bacterial pyrogens (LPS)
-pyrogens pass through a 0.2 µm filter and resist autoclaves

-inject in rabbits and check for temperature change
-LAL (Limulus Amebocyte LysateTest) -> Amebocytes or certain blood cells clot in the presence of pyrogens

Question 39

Environmental Testing:

Answer 39

-Air sampling: Setling plates, slit air sampler, electronic air particle counter, centrifugal air sampler

-Surface sampling: Rodac plates, or swab-rinse test

Question 40

What are the types of Imcompabilites?

Answer 40

30% of drugs are not compatible with the content in an LVP

-Therapeutic: drug-drug interactions -> one will block the effect of the other
-Physical: Precipitation due to solubility problems, turbidity, change of pH, change in color
-chemical: oxidation, hydrolysis, photodegradation

Question 41

Examples of Imcomabilites:

Answer 41

-Therapeutic: Chlorophenymcol and Penicillin antagonize each other

-Physical: Solubility problems, change in color, mixing of basic and acidic drugs in opposite pH

-Chemicals: Ampicillin is prone to hydrolysis in presence of many drugs; Drugs that are light-sensitive and put into a transparent IV bag

Question 42

How are Incompabilites avoided?

Answer 42

-Use as less additives as possible
-Use compatibility guides
-Discard unused solutions after expiration
-Solutions should be freshly prepared and refrigerated -> before infusion thaw to room temperature and check for particles
-check BUDs for compounded preparations
-use Y-site administration to avoid incompatibilities
-incombabilites can be avoided by changing the order (f.e. calcium & phosphate)