A Comprehensive Review of Global Regulatory Guidelines for Parenteral Manufacturing

Parenteral preparations consist of injection gels, implants, solutions, suspensions, emulsions for injection or infusion, and powders for injection or infusion. These are aseptic formulations designed to be administered directly into an animal's or human's systemic circulation by injection. They must meet pharmacopeia-described pharmaceutical quality requirements and are safe for the intended usage, much like other pharmaceutical dosage forms. Both pyrogen-free and sterile parenteral preparations are required. While the pyrogen-free requirement calls for the use of pyrogen-free pharmaceutical ingredients, drug substances, or APIs (Active Pharmaceutical Ingredients), and excipients during the preparation of the sterile drug products in the absence of a dehydrogenation process, sterility can be achieved through a variety of sterilisation procedures that should be suitable for the formulations. Parenteral preparations are a vital component of modern healthcare because they let medications, nutrients, and fluids be directly administered into the bloodstream. his mode of delivery becomes essential when taking medications orally or when prompt therapeutic effects are required. We explore the wide realm of parenteral preparations in this, looking at its many forms, numerous advantages, unique challenges, and vital safety concerns. Parenteral preparations are an integral aspect of modern medicine since they are vital to the direct administration of medications, nutrients, and fluids into the bloodstream. This mode of delivery becomes essential when taking medications orally or when prompt therapeutic effects are required. Parenteral preparations are administered using a range of formulations, including suspensions, emulsions, solutions, and lyophilised powders for reconstitution. Drug molecules are dissolved in the proper solvent to provide rapid and efficient delivery in the most commonly utilised form, solutions. Conversely, emulsions employ immiscible liquid phases to facilitate the administration of lipid-based drugs, some of which might not dissolve completely in aqueous solutions. Suctions, which include solid particles suspended in a liquid medium, can be used to administer medications that are not able to be produced as solutions. Furthermore, because lyophilised powders are stable and portable, they are ideal for a number of drugs and therapies, however reconstitution is necessary prior to usage. Parenteral preparations have numerous advantages over alternative medication administration techniques. Parenteral preparations are medicinal products administered by methods other than oral ones. Insults and transfusion fluids. A sterile solution in an aqueous or greasy medium is injected into the body through one or more layers of the skin and mucous.

Advantages of Parenteral Preparation:

• Parenteral preparation onset of action is rapid
• Parenteral preparation are useful in
• Unconscious patients or unreliable patients
• Patients suffer from vomiting and diarhoe
• Certain parenteral preparation provides prolong drug action e.g. penicillin G provide action up to a month when administered intramuscular route. [3] Parenteral route is sutaible for irritant drug and high first pass
• Transfusion fluid containing nutritives like glucose and electrolytes such as sodium chloride can be given by this route. 
• The drug cannot administer by oral route parenteral route is useful.
• Parenteral preparation is use in emergency cases because onset of action is fast. (such as epilepsy, asthma).

Disadvantages of Parenteral Preparation

• Injection causes pain at the site of administration of drug. Or local irritation as a result of needle insertion ? High cost of production.
• They cannot easily self-administration. Trained persons are required to administered the drug.
• Administration of drug through wrong route of injection may prove to be fatal
• In case drug is overdose it is difficult to save a patient
• There are chances of allergic reaction of a drug by individual. This reaction are very fatal and lead to death
• They required aseptic condition or follow proper aseptic technique during manufacturing
• It poses more risks than the other route
• Parenteral preparation are required aseptic technique during production.

Types of parental products--

[1] Base on Route of Administration.  

1) Intradermal Injection -

These are given in between dermis and epidermis. Skin of the left forearm is usually selected forgiven injection. Generally, 0.1 to 0.2ml of parenteral solution is injected by this route. The route is used for diagnostic purposes and for testing the sensitivity of the injectable For certain substances, administration via an ID route can result in a faster systemic uptake compared with subcutaneous injections, leading to a stronger immune response to vaccinations, immunology and novel cancer treatments, and faster drug uptake. Additionally, since administration is closer to the surface of the skin, the body's reaction to substances is more easily visible. 

Fig.1. intradermal injection.

2) Subcutaneous route (S.C):

These are formed beneath the skin, in the subcutaneous tissue. A volume of 1.0ml or less is typically injected into the upper arm6. This is the most significant route because it is handy for both the patient and the physician. This sort of injection involves inserting a medication into the tissue layer between the skin and the muscle using a small needle. Medication administered this method is typically absorbed more slowly than if injected into a vein, sometimes over 24 hours. This type of injection is employed when other forms of administration may be ineffective. Subcutaneous administration is a popular method for administering several medications due to its high bioavailability and quick onset of effect.

Fig.2. subcutaneous injection.

3) Intravenous Injection-

These injections are administered through a vein and hence straight into the bloodstream. The median basilica vein on the front aspect of the elbow is typically chosen because it is easily accessible and connects to the arm's major veins. A large volume of parenteral fluid, ranging from 1 ml to 500ml or more, can be injected. If more than 15ml of parenteral solution is to be injected, it must be isotonic with blood. Suspensions and greasy injections cannot be injected using this technique. Injections account for approximately 40% of all medications administered in hospitals, and they are used to increase. The many uses of intravenous fluids contribute to the increase in parenteral therapy. The IV fluids continue to be used as a means of fluid alternate, electrolyte balance restoration, supplementary nutrition, and they are also being used as a means of administering other drugs due to convenience, the ability to reduce the annoyance of drugs, and the need for regular and intermittent drug therapy. 

Fig.3.intravenous injection

4) Intracardiac Injection-

The practice of intracardiac injection originated in the 1800s and had been strongly advocated for years before it began to fall out of favor. It was commonly performed throughout the 1960s, as it was thought to be the most expeditious route of drug delivery during a cardiac arrest. By the mid-1970s, the practice of intracardiac injection declined. Safer and simpler routes of medication administration (i.e., intravenous, endotracheal, and intraosseous) became available. Intracardiac injection requires the tip of the needle to be inserted directly through the myocardium and into a cardiac chamber. Echocardiography or bedside ultrasound may be useful in a pericardiocentesis to avoid the lung or myocardium. However, time is of the essence when performing an intracardiac injection. Intracardiac injection should be considered when vascular access is not readily available in a patient in cardiac arrest. The goal of the procedure is to administer epinephrine rapidly to improve the likelihood of achieving a return of spontaneous circulation.

Fig.4. Intracardiac Injection

5) Intrathecal Injection-

Drug delivery into the body can be achieved in several ways, from applying a medicated cream on the skin, to swallowing a pill, to injecting into a muscle or vein. Each route of delivery should at least achieve one thing – getting the drug to the part of the body where it can be helpful. Delivering therapeutic drugs into the brain, however, can be more difficult. Intrathecal injections are used to overcome this challenge.  When a drug enters the body, it travels through the bloodstream until it reaches the target organs. But when a drug is destined to reach the brain, it needs to pass through a unique security feature known as the blood-brain barrier. The blood-brain barrier is important for keeping harmful and unknown substances out of the brain. It turns out that the majority of drugs injected into the body cannot pass this barrier. This poses a challenge for researchers and doctors for delivering important drug treatments to the brain. One way that drugs can be delivered to the brain via the blood is by modifying their chemical nature slightly. This can help with entry through the blood-brain barrier. A more straightforward route of delivery is by injecting drugs into the brain space directly. Your brain inside your head and spinal cord along your back are bathed in and float in a liquid called cerebrospinal fluid (CSF).

Fig.5. Intrathecal Injection-

6) Intracerebral Injection-

(IC) injection of live rabies virus is an invasive and painful procedure. Appropriate IC injection techniques by trained personnel can minimize trauma associated with the technique.  Technical guidance is available in several regulatory guidelines and publications (Bruckner et al., 2003; USDA, 2007; Koprowski, 1996). IC injections can sometimes result in sufficient traumatic tissue damage to cause early death of mice. Accordingly, regulations stipulate that deaths occurring within 5 days of injection are considered nonspecific and not attributable to rabies virus infection. Experienced technical personnel are essential to ensure the collection of consistent and reliable potency data. The use of needles fashioned with a sleeve that provide for a uniform depth of injection is considered helpful (Bruckner et al., 2003).

Fig.6.Intracerebral Injection

[2] Based on volume: - 1. Small volume parenteral – 

An injection that is packed in containers labelled as usally range 1-100 ml in volume., mostly given as multiple dose 

1. Different types
2. Ampule
3. Vials 
4. Dry powder
5. Prefilled syringes

Fig.7.vials

2. Large volume parenteral-

 LVP as product in container labeled as containing more than 100 ml of single dose injection intended for administration by IV infusion. These are injected directly into blood stream (IV preparation) poured into open body cavities and surgical area or introduced into body cavity, they must be sterile, on pyrogenic and free from particulate matter . 

Fig:9. large volume parenteral

[3] Based on composition-

These products can be administered by Intra or extra vascular routes. These LVP are packed into either glass or plastic container of 1 lit. capacity

General Requirements for Parenteral:

• -Sterility
• Free from pyrogens
• Free from particular matter 
• Isotonicity 
• Specific gravity 
• Chemical purity 
• Stability 
• Consideration in Parenteral Preparations:

1. Vehicle: - 

? The vehicles should be pharmacologically inert, on-toxic, compatible with blood, maintain solubility of drug, Chemically and physically must be stable., Pyrogen and microbe free, Not affected by PH., Non-aq. may be used to drug of limited water solubility., It must be safe in amount administered. Eg. fixed oils, peanut oil, Ethyl oleate.

2. Preservatives: -

? It is a substance that prevents or inhibit microbial growth and extends the shelf life of drug products. Antimicrobial preservative, Anti-oxidants, Buffer, Chelating agents, Cryoprotectants, Inert gas, Surfactant and solubilizing agents, Tonicity modifiers, Viscosity modifiers. 

3. Antioxidant: -

To protect formulations from oxidation. There are 2 types- Reducing agents-eg. Thiourea, Ascorbic acid, Sodium bisulfate 0.01%b. Blocking agents-eg. Tocopherol Added to maintain PH for solubility, stability and pain reduction.

4. Cryoprotectants: - 

• Prevent and stabilize denaturation of proteins from effect of freezing.
• Sugar-sucrose, lactose, glucose, trehalose,
• Polyols-glycerol, mannitol, sorbitol
• Amino acid- glycine, alaning, lysine
• Polymers-PEG, dextran, PVP 

5. Lyoprotectants: - 

• Substance which protect drug especially proteins from degradation during drying. 
• Sugar-mannitol, lactose, maltose, maltodextrin, trehalose, sucrose 
• Amino acid-glycin, histadine, arginine]

6. Solubilizing agents and surfactants: - 

1. Substance are used extensively in parenteral suspension for wetting powders and provide acceptable syringe ability. (eg- steroid, fat soluble vitamins) 
2. Must be purified, sterile, pyrogen free. 
3. In limited volume depending on route and type. 
4. Should not vehicles must have special purity and other std. to assure sterility, stability, and safety 
5. Eg-sodium state, fixed vegetable oil, PEG, alcohol

Importance of Isotonicity: -

1. Need an isotonic solution to avoid destruction of RBC, irritation and tissue damage.
2. More important for large volumes, rapidly administered and extravascular injections 3. Reduce pain on injections.
3. Nacl and KCL 
4. Dextrose 
5. Mannitol and Sorbitol 
6. Tonicity modifiers: - To minimize the tissue damage and irritation reduce haemolysis and prevent electrolyte imbalance, product should be isotonic
7. Dextrose (4-5.5%) Nacl(0.5-0.9%)and sodium sulfate (1-1.6%) is used to adjust tonicity.

Fig.10. important of isotonicity

Production Procedure: - 

Production process includes all the steps from accumulation and combining of ingridients of formula to enclosing of product in individual container for distribution. SOP?s are very important.

Flow chart:

Dispensing of raw material and excipients

Washing and depyrogenation of virls, sterilization of rubber stoppers

Manufacturing

Filtraction through 0.2 micro under sterile nitrogen pressure

Filling into vilas through online 0.2 micro cartridge

Seling of vials visual inspection

Labelling and packaging

Final product analysis and release.

Filling and sealing: - 

• The filtered product is filled into final container such as ampoules, vials and transfusion bottles 
• Ampules used for single dose and vials used for filling multidose 
• On small scale filling is done by manually by using hypodermic syringe and needle. ? On large scale filling is done by automatic filling machine ? Filling operations is carried out in aseptic precautions. 
• During filling the ampules, the care should be taken that solution be filled below the neck og ampules.
• Sealing should be done immediately after filling.
• Ampoules are sealed by manually by rotating neck of ampule in flame of Bunsen burner on small scale. 
• Ampules are sealed by ampule sealing machine is used in which tip of ampule is used to fused to seal it on large scale.
• Rubber closure must fit opening of container snugly enough to produce seal.
• A faster hand method involves picking up closure and inserting it into vials by means of tool connected to vacuum line.

Sterilization and packaging; - 

1. Sterilization of product: -

This process is applicable to manufacture of certain pharmaceuticals and biological that is thermobile. The rate of drying depend on the thermal conductance of frozen product. Freeze driers are usually operated by an automatic control system. The product is usually processed until there is less than 1%moisture in dried material. Eg. Multiple vitamin combinations, antibiotics, hormones, tissue section. Equipment and containers should be cleaned. Glassware and metalware is automatically conveyed, usually in an inverted position through series of rigorous, high pressure treatment including hot detergent, hot tap water and final rinse with distilled water. 

2. Packaging of product: -

It is important part of product. It must be particularly dignified, neat and attractive appearance if it is to convey to user the quality, purity and reliability.  The packaging should be protect the product against the physical damage during shipping, handling and storage.

Storage and Distribution: -  

The storage and distribution as important as production. Opthalmic preparations should maintain their integrity throughout their production. WFI (water for injection) should not be held for more than 24 hrs at room temperature before it is used, but if held at 80? C. The distribution may be by direct withdrawal from tank or in large plants through pipe system.

Formulation of Parenteral Preparation--

Formulation of Parenteral

1. Vehicle
2. Additives

1. Vehicle: These are used for carrying the drug substances or dissolving the drug.They are two types: a) aqueous vehicles, b) Non-Aqueous vehicles

a) Aqueous vehicles: 

water is used as vehicle for majority of injections because water is tolerated well by the body and is safest to administer. The aqueous vehicle used are e.g.: Water for injection.

Water for injection [WFI]:  Water for injection is the most widely used solvent for parenteral preparation

4. Preparation:   The source water usually must be pre-treated by one or combination of the following treatments: Chemicals softening, Filtering, deionization, carbon absorption, or reverse osmosis purification. Preparation for water for injection is shown below:

1.Cleaning. 

2.Preparation of bulk products. 

3.Filtration. 

4.Filling of solution in or product in ampule or vail. 

5.Sealing. 

6.Sterilization. 

7.Test for quality control

WFI can be prepared by distillation or by membrane technologies (reverse osmosis or ultrafiltration) USP: “distillation or a purification process that is equivalent of superior to distillation. 

B) Non-Aqueous vehicles:

2. Additives: The USP includes in this category all the substances added to a preparation to improve or safe guard its quality. The adjuvants should be used only when it is absolutely necessary to use them9

Commonly used additives: ---

a) Solubilizing agents:   These are used to increase solubility of drugs which are slightly soluble in water. The solubility of drugs is increased by using surface-active agents like tweens and polysorbates or by using co-solvents10. e.g.: dimethylacetamide, Dioctyl sodium sulfosuccinate

b) Stabilizers:  The drugs in the form of solutions are more liable to deteriorate due to oxidation and hydrolysis. The stabilizers are added in the formulation to prevent this. The oxidation can be prevented by adding a suitable anti-oxidant, such as, thiourea, ascorbic acid sodium meta bisulphate or the product is sealed in an atmosphere of nitrogen or carbon dioxide. Hydrolysis can be prevented by using a non-aqueous vehicle or by adjusting the pH of the preparation e.g. Creatinine, glycine, Niacinamide, Sodium caprylate

c) Antimicrobials:   These substances are added in adequate quantity to prevent the growth of microorganisms during storage. So, these substance act as preservatives. Antibacterial agents are added in single dose container where parenteral products are sterilised by filtration method and in multi task containers to prevent microbial contamination12. e.g.: Benzyl alcohol, Benzalkonium chloride, Butyl-P-Hydro benzoate, Thymol cresol Chloral butanol, phenol.

d) Buffering agents: The degradation of the preparation which is due to the change in PH, can be prevented by adding a suitable buffer to maintain the desired PH. Buffer systems must be selected with consideration of their effective range, concentration and chemical effect on the total product13. e.g.: citric acid, sodium citrate, Acetic acid, Sodium acetate.

e) Chelating agents:   Chelating agents are added in the formulation, to chelate the metallic ions present in the formulation. They form a complex which gets dissolved in solvents14. e.g. EDTA, Citric acid, Edentate disodium, Edentate calcium di sodium. 

f) Suspending agents: The suspending agents are used to improve viscosity and to suspend the particles for a long time.e.g. Methyl cellulose, Gelatine& Acacia, Carboxy methyl cellulose.

g) Emulsifying agents:    Emulsifying agents are used in sterile emulsions. For this purpose, lecithin is generally used.e.g.: Lecithin’s, Beeswax.

h) Wetting agents:    The wetting agents are used to reduce the interfacial tension between the solid particles and the liquid. So as to prevent the formation of lumps. They also act as antifoaming agents to subside the form produced during shaking of the preparation e.g. PEG, Theophylline, Povidone, polysorbate. 

i) Cryoprotectants & Lyoprotectants: These are additives that serve to protect biopharmaceuticals from adverse effects due to freezing or drying of the product during freeze dry processing.: sugar such as sucrose, PEG, Dextrin, Glycine &lysine.

j) Tonicity factors:   Parenteral preparation should be isotonic with blood plasma or other body fluids. The iso tonicity of the solution may be adjusted by adding sodium chloride, dextrose and boric acid etc. ..., in suitable quantities. These substances should be compatible within sotheir ingredients of the formulation. 

Quality control test for parenteral product: -

1. Pyrogen test: 

  a. LAL test 

  b. Rabbit test 

2. Sterility test

3.Leakage test

1. Pyrogen test: -Detection of endotoxins via LAL test and rabbit test Pyrogens are product of metabolism of microorganism gram negative bacteria produce MOA potent pyrogen. When these pyrogens introduce in body produce fever with acne. The test performed to detect presence of pyrogen is

Lal Test --

LAL reagent    it is lystate of ameboytes obtained from horseshoe crab only it is in vitro test

Combination of 0.1 test sample with lal reagent

Mixer is analysed for presence of gel colt

Positive test indicates presence of endotoxins

Rabbit test --

Injection the solution on rabbit vein

The temperature sensing probe into rectum cavity at depth 7.5 cm

Warm test solution 37C

Initially perform on three rabbit