2. INTRODUCTION
• Parenteral (Gk, para enteron, beside the intestine) dosage forms differ from
all other drug dosage forms, because they are injected directly into body tissue
through the primary protective systems of the human body, the skin, and mucous
membranes. They must be exceptionally pure and free from physical, chemical,
and biological contaminants. These requirements place a heavy responsibility on
the pharmaceutical industry to practice current good manufacturing practices
(cGMPs) in the manufacture of parenteral dosage forms and on pharmacists and
other health care professionals to practice good aseptic practices (GAPs) in
dispensing parenteral dosage forms for administration to patients.
3. • Certain pharmaceutical agents, particularly peptides, proteins, and many
chemotherapeutic agents, can only be given parenterally, because they are
inactivated in the gastrointestinal tract when given by mouth. Parenterally-
administered drugs are relatively unstable and generally highly potent drugs that
require strict control of administration to the patient. Due to the advent of
biotechnology, parenteral products have grown in number and usage around the
world.
4. CHARACTERISTICS OF PARENTERAL
DOSAGE FORMS
• Parenteral products are unique from any other type of pharmaceutical dosage form
for the following reasons:
• All products must be sterile.
• All products must be free from pyrogenic (endotoxin) contamination.
•Injectable solutions must be free from visible particulate matter. This includes
reconstituted sterile powders.
•Products should be isotonic, although strictness of isotonicity depends on the route
of administration.
• Products administered into the cerebrospinal fluid must be isotonic.
• Ophthalmic products, although not parenteral, must also be isotonic. Products to
be administered by bolus injection by routes other than intravenous (IV) should be
isotonic, or at least very close to isotonicity.
5. • IV infusions must be isotonic.
• All products must be stable, not only chemically and physically like all other
dosage forms, but also ‘stable’ microbiologically (i.e., sterility, freedom from
pyrogenic and visible particulate contamination must be maintained throughout
the shelf life of the product).
•Products must be compatible, if applicable, with IV diluents, delivery systems, and
other drug products co-administered.
6. CLASSIFICATION
Injections may be classified in six general categories:
1. Solutions ready for injection
2. Dry, soluble products ready to be combined with a solvent just prior to use
3. Suspensions ready for injection
4.Dry, insoluble products ready to be combined with a vehicle just
prior to use
5. Emulsions
6. Liquid concentrates ready for dilution prior to administration
7. COMPONENTS
• Components of parenteral products include the active ingredient, formulation
additives, vehicle(s), and primary container and closure. Establishing
specifications to ensure the quality of each of these components of an injection is
essential. Secondary packaging is relevant more to marketing considerations,
although some drug products might rely on secondary packaging for stability
considerations, such as added protection from light exposure for light- sensitive
drugs and antimicrobial preservatives.
8. SOLVENTS AND VEHICLES
WATERAND AQUEOUS VEHICLES
- Water for injection
- Sterile water for injection
- Bacteriostatic water for injection
- Sodium chloride injection
-Bacteriostatic sodium chloride injection
NON-AQUEOUS SOLVENTS
-Fixed vegetable oils
-Alcohols
9. ADDED SUBSTANCES
PRESERVATIVES
- Agents containing mercury in concentration not more than 0.01%
- Cationic surfactants
- Alcohols up to 2%
- Phenols up to 0.5%
- Others
14. LABELLING
• Name and concentration of active substances
• Name and concentration of any added antimicrobial preservatives
• Route of administration
• Shelf- life
• Batch number
16. CONTAINERS AND CLOSURES
• Injectable formulations are packaged into containers made of glass or plastic.
Container systems include ampoules, vials, syringes, cartridges, bottles, and bags.
17. • Ampoules are all glass, whereas bags are all plastic. The other containers can be
composed of glass or plastic and must include rubber materials, such as rubber
stoppers for vials and bottles and rubber plungers and rubber seals for syringes
and cartridges.
• Irrigation solutions are packaged in glass bottles with aluminum screw caps.
• Further, the integrity of the container/closure system depends on several
characteristics, including container opening finish, closure modulus, durometer
and compression set, and aluminum seal application force
21. CALCULATION INVOLVED IN PREPARATION OF
ISOTONIC PARENTERAL SOLUTIONS
Freezing point depression (colligative properties)
• - 0.52 is the freezing point of both blood serum and lacrimal fluids
Rault equitation:
ΔТm- freezing point depression (°C)
Km- molar constant of freezing depression point of water (-1.86°C l/mol )
m- weight of substance in isotonization solution (g) i-
number of dissociated ions in the electrolyte
Mr- molecular weight
V- volume of solution for isotonization
22. D- value (Tabular Value)
- Freezing point depression of electrolytes
- Proportional of concentration of dissolved substance
23. CALCULATION INVOLVED IN PREPARATION OF
ISOTONIC PARENTERAL SOLUTIONS
NaCl equivalent
- Weight of NaCl in grams dissolved in 1000 ml of water, which gives the
same freezing point depression like 1 gr of the active substance, dissolved in
equal volume of distillated water
- X- weight (g) of the substance for isotonization
- Cx- weight of the solution required for isotonization of 100 ml water
- V- volume of solution required for isotonization
- a- weight of the active substance
- E- NaCl equivalent of active substance
- Ax- NaCl equivalent of substance for isotonization (for NaCl=1)
24. CALCULATION INVOLVED IN PREPARATION OF
ISOTONIC PARENTERAL SOLUTIONS
V- value
Tabular value which represents the volume of water in ml, which needs to be added
of 0.3 g of active substance in order to prepare isotonic solution
V-value
x ml water
0.3g active substance
x g active substance
25. CALCULATION INVOLVED IN PREPARATION OF
ISOTONIC PARENTERAL SOLUTIONS
Example:
How much NaCl (g) is required for isotonization of 0.1 % 1000 ml solution
of procaine hydrochloride?
1. Freezing point depression method:
ΔТm=?
• Mr(procaine hydrochloride)= 282.78 g/mol
100ml
1000ml
• 0.1g
• X g
• X= 1 gr
ΔТm=0.0131
27. D- value
D-value (procaine hydrochloride 1%)=0.122
0.122
X
1%
0.1%
X= 0.0122 ΔТm
0.52-0.0122=0.507
0.9% 0.52
X% 0.507
X=0.877%
0.877g 100ml
X g 1000ml
X= 8.775g NaCl
28. E- value (NaCl equivalent)
E-value (procaine hydrochloride)=0.21
8.79g NaCl
29. V- value
V-value (procaine hydrochloride)=7
7ml
Xml
0.3g
1g прокаин хидрохлорид
X=23ml
1000ml-23ml=977ml
0.9g
Xg
100ml
977ml
X=8.79gNaCl
30. TOP 7 REGUALTORY REQUIREMENTS FOR
INJECTABLE PHARMACEURTICALS
Gels, ointments, lotions, and pills, oh my! Drug products come in all sorts of
formulations, shapes, and sizes. However, injectable products require sterility
of the drug product (dosage form) due to their route of administration. Unlike
most products, injectables have increased requirements because injectable
products can avoid our body’s natural skin barriers and digestive tract barriers
to toxins. Keep reading to learn how these seven regulatory requirements apply
to your pharmaceutical product.
31. Regulatory Requirement #1: Safety
• Most sterile pharmaceuticals are injected directly into the body and avoid
the body’s natural barriers to infection (skin) and metabolite breakdown
(digestive tract).
• Thus, sterile injectables must be safe for the body to be exposed to at the
quantity of the therapeutic dose. Even water, in large enough quantities, is
unsafe to the human body.
• Depending on the pharmaceutically active ingredient, sterile dosage forms
can be easier or more difficult than nonsterile dosage forms. This is
because a limited number of additives can be used as the active
pharmaceutical ingredient for sterile injectables due to the increased safety
considerations.
32. • When considering drug solubility, controlled or sustained delivery,
stability, and tonicity, make sure that suitable, FDA-approved additives are
available for your active ingredient before moving forward with an
injectable formulation.
• Otherwise, expect to spend additional time and money acquiring data to
prove the safety of the new additives in your injectable formulation.
Required safety date is often time-consuming to obtain as the Kefauver-
Harris Amendments to the Federal Food, Drug, and Cosmetic Act require
most pharmaceutical preparations to be tested for safety in animals.
• Safety testing in animals is required as even a product that passes sterility
testing, endotoxin testing, and chemical analysis can still have unexpected
toxicity when injected.
33. • The FDA and USP provide instructions for safety evaluations of
pharmaceutic excipients. Also, the International Pharmaceutical Excipients
Council (IPEC), a regional collaboration of the United States, Europe, and
Japan, covers excipient safety and public health issues connected with
international trade.
• Over 200 national and multinational excipient makers and producers and
the companies that use these excipients in finished drug dosage forms are
members of one or more of the three IPEC regions.
34. Regulatory Requirement #2: Sterility
• Achieving and maintaining product sterility are among the greatest
challenges manufacturers face for injectables since most rely on aseptic
manufacturing.
• In aseptic manufacturing environments, product processing requires
excluding microorganisms from the manufacturing methods. There are
many validation steps to maintain sterility.
• Some of these validation steps include valid sterilization procedures for all
components during manufacturing of the product, a proper method for
sterile aseptic filtration, maintenance of ISO-certified clean rooms,
validation of aseptic processes, training and application of good aseptic
practices by contract manufacturing organizations, use of antimicrobial
preservatives for multiple-dose products, proper testing of container-
closure integrity, and proper testing for overall product sterility.
35. Regulatory Requirement #3: Freedom From Pyrogenic
Contamination
• Pyrogens are fever-producing molecules that are primarily microbial.
• Microbial pyrogens are known as bacterial endotoxins. If injected at a high
enough concentration, pyrogens can lead to fever, illness, and (in extreme
cases) death. Limulus Amebocyte Lysate (LAL) endotoxin testing can
detect and quantify bacterial endotoxins. For an injectable product to be
marketed, it must be LAL tested and meet strict endotoxin limits expressed
by λ. If your injectable does not meet its endotoxin limit, certain
depyrogenation methods can be used to reduce endotoxins from the
manufacturing and packaging of injectable products.
• Some of these methods are improved cleaning validations, additional
depyrogenation cycles for glassware, improved pyrogen/endotoxin
removal from rubber closures, depyrogenation of water systems, and use of
endotoxin-free raw materials.
36. Regulatory Requirement #4: Freedom From Visible
Particulate Matter
• Visible particulate matter in a liquid implies poor product quality and
safety.
• Ready-to-use solutions and reconstituted solutions must be free from
visible particulate matter and meet criteria for subvisible particles of
specific sizes.
• Some of the ways particulate matter can sneakily enter a product during
exposure to manufacturing equipment and packaging materials, solution
filtration procedures, manual manipulation by manufacturing personnel,
and the addition of product solutions or additives.
• Additional validations for equipment cleaning, personnel training,
cleanroom cleanliness, raw material sourcing and preparation, and
filtration processes can support in eliminating issues with particulate
matter.
37. Regulatory Requirement #5: Stability
• All pharmaceuticals have stability requirements. They must be stable under
established manufacturing, packaging, storage, and usage conditions. In
addition to traditional stability, injectables need to be chemically and
physically stable throughout the product’s shelf-life.
• Except for solubility challenges, solving stability problems occupies most
product development time and effort.
• Injectable therapeutic peptides and proteins offer additional stability
challenges.
• The temperature, light, pH, shear, metallic impurities, oxygen, and more
must be considered to keep these biologics active with peptides and
proteins.
• Storing, shipping, and handling of the active pharmaceutical ingredient
affect the stability of chemical therapeutics.
38. • Stability challenges compound with the mixing, filtration, filling,
stoppering, and sealing of the product.
• Many injectable drugs are so unstable in a solution that they must be stored
in a solid-state long term. Thus, lyophilization processes and maintaining
stability during lyophilization add further challenges to product
development.
• Unlike unsterile medical products, sterile dosage forms must
simultaneously address stability and sterility challenges. In other words,
injectables must maintain chemical stability, physical stability, and sterility
throughout the entire shelf-life and usage of the product.
• Thus, maintaining stability in the final container-closure system while
being stored, shipped, and manipulated before being administered to
people or animals ends this marathon of developmental stability challenges
injectable products face.
39. Regulatory Requirement #6: Compatibility
• Most pharmaceutical formulations are ready-to-use products that do not
require preparation by patients or health care professionals before
administration.
• However, many injectables require manual preparation prior to injection.
In particular, freeze-dried parenteral products must be reconstituted before
use.
• This manual manipulation step means that the sterile, freeze-dried product
must show compatibility with the diluents used for reconstitution.
• If the parenteral is a multi-drug infusion, pharmaceutical companies must
show that the two or more drugs in the infusion system are compatible.
40. Regulatory Requirement #7: Isotonicity
• Isotonicity, loosely translated, means “the same tone.” Human cells maintain a
certain “tone” to support optimal function within the body.
• This “tone” is a certain biological concentration of ions, molecules, etc., that gives
cells unique properties.
• For injectables, the most critical component of isotonicity to regulate is our cells’
osmotic pressure.
• Osmotic pressure differences result in water migration across cellular membranes.
• Osmotic pressure itself is an equilibrium pressure where no water migrates across
the cell’s membrane.
• Solutions can be hypertonic (have a greater osmotic pressure than our cells),
hypotonic (have less osmotic pressure than our cells), or isotonic (have the same
osmotic pressure of our cells). Hypotonic injections can cause cells to swell to the
point of bursting.
41. • Conversely, hypertonic injections cause cells to shrink. Cell shrinkage is also
known as crenation. Thus, injectable formulations should be isotonic and prevent
cells from swelling or shrinking within the body.
• Large-volume intravenous injections and small-volume non-intravenous injections
must be isotonic to avoid pain, tissue irritation, and more physiological severe
reactions.
• Small volume intravenous injections are more forgiving and do not have to be
isotonic.
• Small volume intravenous injections will only damage a small number of red blood
cells which the body can readily replace.
42. SUMMARY
Overall, sterile dosage forms are needed for injectable products. Injectables have
higher requirements for safety, sterility, pyrogenicity, particulate matter, stability,
compatibility, and isotonicity since they circumvent our body’s traditional barriers to
toxins. Regarding safety, safety testing is often lengthy since animal testing is
required. When it comes to injectables, maintaining sterility can be tricky as aseptic
manufacturing conditions must be maintained. Injectables must pass a LAL test for
pyrogens as well as exclude all visible and certain subvisible particles. Injectables
must be compatible with any agents used for reconstitution or any drugs used in a
multi-drug infusion. Stability offers a marathon of challenges from active
pharmaceutical manufacture to reconstitution and end-use in patients. Injectable
liquids must have the same osmotic pressure as our biological cells to prevent the
swelling or the shrinking of our critical cells, tissues, and organs). Luckily, many
contract manufacturing organizations can support you with passing these seven
regulatory hurdles and getting your novel injectable product on the market.
