MANUF LAB - Parenterals

Sterile products

These are products that are going to be administered using an enteral route of administration.

Sterile

Sterile products are going to be infused directly into the bloodstream or body tissue, it is extremely important they be ___________

Microorganisms

Sterile products are prepared in a sterile manner, which means free from contaminating ____________

Sterility

________________ is of utmost importance, since it is introduced or directly placed in direct contact with the internal body fluids or tissues, where infections can easily arise

Solutions, suspensions, pellets

[Characteristics of sterile products] Most frequently in a form of ________ or ___________, or maybe __________ for tissue implantations

Microbial contaminants and toxic components

[Characteristics of sterile products] Free from ________ contaminants and ____________ components

Purity

[Characteristics of sterile products] Of exceptional high level of __________

When rapid drug action is desired, as in emergency cases; When the patient is uncooperative, unconscious, or unable to accept oral medications; When the drug itself is ineffective by other routs.

Conditions/Situations when parenteral routes are undertaken (3)

Large Volume Parenterals (LVP) and Small Volume Parenterals (SVP)

Classes of Sterile Products;

LVP and SVP

Sterile, pyrogen-free preparations intended to be administered parenterally

Pyrogens

Fever producing organic substances arising from microbial contamination and are responsible for many of the febrile reactions.

Febrile reactions

It occurs in patients following IV injections of a pyrogen-contaminated injectable product

Chilling, malaise, pain at the back

symptoms of febrile reactions

PVC; Polyolefin collapsible bags; Type 1 vials

Large Volume Parenterals are packaged in _______ or _______ collapsible bags or glass (type ______) vials

250 mL, 500 mL, 1000 mL

Fill capacities of LVPs (3)

100-1000 mL

LVPs are administered in volumes of ____ to _____ amounts and more per day by small IV drip sets, with or without controlled infusion rate systems.

Bacteriostatic

LVPs should not contain ________ agents or other pharmaceutical additives

For Maintenance Therapy and Replacement Therapy Purposes

LVPs are used for ________ and ________ purposes

0.9% NSS

[Examples of LVPs] Isotonic vehicle

D5W, D10W

[Examples of LVPs] electrolyte replenisher

Normosol Solution, Maintenance Solution

[Examples of LVPs] Nutrient

Lactated Ringer's Solution

[Examples of LVPs] Systemic alkalinizer

Ringer's Solution

[Examples of LVPs] Nutrient, alkalinizer

Mannitol injection

[Examples of LVPs] Diuretic

Single dose (ampule); Multiple Dose (vial) containers

SVPs can be packaged in single dose (________) and multiple dose (________) containers

0.5 mL to a maximum of 30 mL

SVPs have fill volumes as little as ______ mL to a maximum of ______ mL

Caffeine and Sodium benzoate injection

[Examples of SVPs] cardiac and respiratory stimulant

Procaine hydrochloride injection

[Examples of SVPs] local anesthetic

Insulin injection

[Examples of SVPs] anti-diabetic

Irrigation fluids

Solutions intended to bathe or wash wounds, surgical incisions or body tissues

Sterile water for irrigation

[Examples of Irrigation fluids] vehicle

Acetic acid for irrigation

[Examples of Irrigation fluids] washing blood and surgical debris

Sodium chloride for irrigation

[Examples of Irrigation fluids] as topical wash for wounds and as enemas

Ophthalmic preparations

Sterile products free from foreign particles and are packaged for instillation into the eye

Solutions, ointments, and pellets

Ophthalmic preparations come in _______ (3)

Sterility

The single dominant factor of ophthalmic preparations is specification for ______________ (regardless of form, substance, or intent)

Dialysis

It is a process whereby substances are separated from one another in solution, by taking advantage of their differing diffusibility through membranes

Poisoning, kidney failure, patients awaiting renal surgical procedure or kidney transplants

Dialysis is a life-saving procedure in cases of ______________

Peritoneal dialysis solutions

Type of dialysis solutions that is allowed to flow into the peritoneal cavity to remove toxic substances normally excreted by the kidney

Peritoneal dialysis solutions

Type of dialysis that contains dextrose, vitamins, minerals, electrolytes, and amino acids or peptides

Hemodialysis solutions

Solutions employed to remove toxins from the bloodstream

Biologicals

These products are intended for administration by injection and are packaged and labeled in the same manner as other single dose SVP (in ampules or prefilled syringes)

2-8 deg C

Storage of biological is in a refrigerator temperature between _____ to _____ deg C. FREEZING MUST BE AVOIDED

A year or longer (usually 1 and a half years)

The expiry date of biologicals is ___________ after manufacture

Biologicals

Injectables which exert various immunologic effects

Vaccines, toxins, toxoids, antitoxins, antiserums, diagnostic aids, blood derivatives

Pellets/implants

Small, sterile cylindrical-shaped objects by compression without excipients/additives

3.2 mm by 8 mm

Dimensions of a pellet

Pellets/Implants

It provides continuous release of medication over a prolonged period of time; These are implanted under the skin (thigh, breast, abdomen, upper arm) with a special injector device or by minor surgical incision

Levonorgestrel implants

[Examples of pellets] used as contraceptive (up to 5 years)

Estradiol and testosterone implants

[Examples of pellets] for HRT

Research and Product development

First division of manufacturing areas for sterile product preparation

Sterile and therapeutically effective

The ultimate goal is to develop a parenteral product that is ________________

Effect of route of administration

[Factors to be considered in the development of parenteral product] 1st factor

NMT 0.2 mL is given due to slow absorption

[volume in which the dose of a drug is given] Intracutaneous volume in which the dose of a drug is given

About 1 mL or less

[volume in which the dose of a drug is given] subcutaneous

About 10 mL or less

[volume in which the dose of a drug is given] intraspinal

About 250 mL for infusion sets; about 20 mL or less (syringe)

[volume in which the dose of a drug is given] intravenous (LVP's)

IM Injections

ns are preferred for _____ injections

Nature of drug preparation

[Factors to be considered in the development of parenteral product] 2nd factor

Aqueous solutions

[Nature of drug preparation] _____________ solutions give faster effect than suspensions, emulsions, and pellets

Suspension and emulsion

[Nature of drug preparation] In ____________- and _______________ form, there is further retardation of the absorption rate of the drug

Isotonic

[Nature of drug preparation] For IV and intraspinal routes, the aqueous or solution form is preferred. It should be ___________

Hypertonic

[Nature of drug preparation] For IM and SC routes, slightly ______________ solutions aid in increasing absorption of drugs

IM Injections

[Nature of drug preparation] Oleaginous solutions are preferred for ______ injections

water

The most frequently used vehicle is _________, since it is vehicle for all natural body fluids.

Water for Injection

Superior quality requirement for aqueous vehicles is described under _____________________ USP

NaCl injection (NSS), Dextrose injection (D5W, D10W), Dextrose and NaCl injection, lactated ringer's injection

Fixed oils

The most important group of non-aqueous vehicles are the ___________, USP provides specifications for such vehicles

Ethyl oleate, isopropyl myristate, benzyl benzoate, polyethylene glycol, propylene glycol

Other non-aqueous vehicles (5)

Must be of vegetable origin for faster metabolism, must remain liquid at room temp (contain esters of unsaturated fatty acids), Must not become rancid rapidly (anti-oxidants maybe added to retard oxidation)

USP Specifications for fixed oils as parenteral vehicles

Gram negative

Vehicles in irrigation and parenteral solutions should be rendered free from pyrogens. ______________ bacteria produces the most potent pyrogenic substances, although gram positive and fungi can also produce pyrogens

Water, Equipment, Solutes, manufacturing methods

Sources of pyrogens (4)

Proper distillation methods, proper storage to prevent growth of microorganism

Pyrogen-free water is produced through __________-

Glass

Pyrogenic materials strongly adhere to ______________ and other surfaces

Adequate cleaning and washing SOP's, Dry Heat depyrogenation procedures

When residues of solutions in used bottles often become bacterial culture from septic patients or environment, follow ___________ (2)

Re-crystallization and washing precipitates

Solutes may be crystallized or precipitated from aqueous liquids containing pyrogenic contaminants. In such cases, the solutes must be purified by _____________ (2)

Sterilization nad production should be finished within ____________ working day only

240 deg C for 45 mins, 650 deg C for 1 minute, 180 deg C for 4 hours

Dry heat settings

Antimicrobial agents, buffers, tonicity agents, anti-oxidants

Added substances for parenteral preparations

Non-toxic, should not interfere therapeutic efficacy of the product, should not interfere with the assay of the active/s, should be present and active until the expiry date

Characteristics of added substances (4)

Multiple dose

USP states that antimicrobial/fungistatic agents must be added to preparations contained in __________ dose containers

Antimicrobial agents

It must be present at adequate concentrations at the time of use of the product to prevent the multiplication of microorganisms

Compatibility

Antimicrobial agents must be studies with respect to _____________ with other formulation ingredients

Tonicity contributors

Compounds contributing to the isotonicity of the product; it reduce the pain of injection in areas with sensitive nerve endings

Buffers

Stabilize the solution against chemical degradation that might occur if the pH is changed appreciably.

Acid salts

These are the most frequently employed buffers

Citrates, acetates, phosphates

Examples of acid salts

Antioxidants

Frequently required to preserve products from oxidative degradation

Sodium bisulfite

The common choice of antioxidant of formulators

Acetone sodium bisulfite, sodium formaldehyde sulfoxylate. Thiourea

These are also used as anti-oxidants

Type I

[Glass types] Generally soluble for all parenterals

Type II

[Glass types] Treated with sulfur dioxide, suitable for parenteral solutions which are buffered, with pH below 7 and not reactive with glass

Type 3

[Glass types] Suitable for anhydrous parenteral liquids or dry substances

Type NP

[Glass types] Not for parenteral use. Suitable only for extractives

Low-density polyethylene (LDPE) polymer

Material of the plastic container for eye preparations

Rubber closures

These are used to seal the openings of cartridges, vials, and bottles. By providing a material that is soft and elastic enough to permit entry and withdrawal of a hypodermic needle.

Metal caps

For parenteral products, metal such as aluminum caps is used to crimp the rubber closures in place

Freezed Dried/Lyophilized Parenteral products

Process involves removal of water from the parenteral solution, by sublimation, after it is frozen

Freezed Dried/Lyophilized Parenteral products

This process is only applicable to thermos-labile or unstable drugs in aqueous, liquid form