Pharmaceutical liquid injections

• Biologics - Biologics are derived from living cells and include complex proteins, blood products, vaccines, etc. They are produced using biotechnology techniques and have a sensitive molecular structure.

• Highly potent APIs - These APIs demonstrate pharmacological effects even at very low concentrations. They require specialized handling to control exposure risks.

Sourcing high-quality APIs is critical for injectable pharmaceuticals. Manufacturers must audit suppliers and assess factors like cGMP compliance, process validation, consistency in quality, and supply reliability. Stringent specifications are set for API quality control testing including identification, assay, impurities, residual solvents, microbiological attributes, etc. Proper analysis and documentation ensures the APIs meet established safety, quality and purity standards before being used in pharmaceutical formulations.

paracetamol inj 300mg

paracetamol inj 500mg

pharmaceutical liquid injections Excipients

Excipients play a critical role in pharmaceutical liquid injections. They serve various functions including:

• Bulking agent - To increase the volume of the product. Examples include mannitol and lactose.

• Buffering agent - To maintain pH and ensure drug stability. Common examples are phosphates and citrates.

• Surfactants - To increase solubility of APIs. Polysorbates and cremophor are often used.

• Preservatives - To prevent microbial growth. Parabens and benzoates are typical preservatives.

• Antioxidants - To prevent oxidation and degradation. Ascorbic acid and sodium metabisulfite can provide antioxidant effects.

• Chelating agents - To improve drug stability by binding metals. EDTA is a widely used chelator.

• Tonicity agents - To control osmotic pressure and prevent pain on injection. Includes salts like sodium chloride.

The selection of appropriate excipients is critical. Factors like compatibility with the API, pH stability, sterilization method, osmolality, and intended delivery device must be considered during formulation development. Quality excipients from reputable suppliers should be used. Excipients comprise the majority of an injectable product, so their qualities and properties heavily influence the overall safety and efficacy.

paracetamol inj 300mg

paracetamol inj 600mg

Pharmaceutical liquid injections Formulation

The formulation process is crucial in pharmaceutical liquid injection manufacturing. The active pharmaceutical ingredients (APIs) and excipients must be combined in a way that ensures the drug product is effective, stable, sterile, and safe for patients.

Several factors must be considered during formulation:

• Solubility - The API must fully dissolve in the selected solvents/vehicles. Solubility depends on the chemical properties of the drug substance as well as temperature, pH, and other factors. Solubility studies help determine the best solvent system and process parameters.

• Stability - The formulated product must remain chemically and physically stable over the desired shelf life. Stability is affected by temperature, light exposure, oxidation, hydrolysis, and interactions between ingredients. Accelerated stability studies identify optimal storage conditions.

• pH - The pH of the formulation directly impacts drug solubility and stability. Buffers may be added to maintain an optimal pH range. The pH also affects comfort during injection and compatibility with containers.

• Sterility - Sterile filtration is performed after formulation to remove any microbes. The formulation components should not promote microbial growth. Preservatives may be added if the product contacts multiple dose containers.

• Safety - The osmolarity, viscosity, and irritancy of the formulation must be acceptable for patient comfort during injection. Toxicity concerns of both APIs and excipients are evaluated.

Careful formulation design is required to produce a high-quality injectable medicine that is safe and effective for patients. The most appropriate solvents, stabilizers, buffers, and processing conditions must be selected based on drug properties and dosage form requirements.

paracetamol inj 300mg

paracetamol inj 600mg

Pharmaceutical liquid injections Filtration

Filtration is a critical step in pharmaceutical liquid injection manufacturing to remove particulate matter that could clog injectors or induce immunogenic reactions. Strict filtration is required at multiple steps of production to achieve sterility and patient safety.

There are several types of filters used:

• Sterilizing grade filters - Membrane filters with a pore size of 0.22 microns or smaller are used for final sterilization of solutions before filling. These remove bacteria and particles. Common materials are cellulose acetate and polyethersulfone.

• Clarifying filters - Larger pore size filters around 1-5 microns are used earlier in production to remove undissolved particles and impurities while allowing dissolved molecules to pass. Clarifying helps improve the sterilizing filter lifespan.

• Venting filters - Hydrophobic microporous membrane filters are used to allow gases to vent while preventing ingress of microorganisms during liquid filling.

• Bioburden reduction filters - Filters around 0.45-0.65 microns are sometimes employed after initial sterilization but before final fill to further reduce bioburden.

Proper filtration is important to remove pyrogenic substances, improve drug stability, provide sterility assurance, and prevent machine blockages. Filters must be integrity tested after use to check for defects. Overall, filtration is a multifaceted process fundamental to safe pharmaceutical injectable manufacturing.

Pharmaceutical liquid injections Filling

Filling is a critical step in pharmaceutical liquid injection manufacturing that involves transferring the sterilized formulation into containers while maintaining sterility. This is accomplished using specialized filling machines and equipment designed for aseptic processing.

Filling Equipment

• Peristaltic pumps: Used to transfer sterile liquid formulations into containers in a non-contact manner. The fluid moves through a tube that is compressed by rollers to push the liquid forward without exposing it to the environment.

• Time/pressure filling machines: Use pressure and vacuum to fill containers at high speeds with great accuracy. Containers move under filling nozzles synchronized to dispense precise volumes.

• Syringe fillers: Automate the filling and stoppering of syringes. Syringes are oriented, filled to a target volume, and stoppers are inserted at high speeds.

• Blow-Fill-Seal: An automated process where containers are formed from plastic, filled with solution, and sealed in a continuous operation. This creates a hermetically sealed container without human intervention.

Quality Control

Strict protocols are followed to ensure filling quality and sterility. These include:

• Operator training and gowning - Operators are fully gowned wearing masks, hair nets, gloves, booties, etc. to prevent contamination.

• HEPA-filtered environment - Filling rooms have HEPA filters for particulate control and laminar air flow over critical areas.

• Sterilization of equipment - All product contact parts are sterilized between batches with steam, autoclave or gamma irradiation.

• Container inspection - Containers are visually inspected for defects and integrity before filling. Automatic inspection systems may also be used.

• Weight checks - The fill weight of containers is checked to ensure proper volumes are dispensed.

• Media fills - Simulated fills are done periodically to confirm aseptic techniques. The media is incubated to check for microbial contamination

paracetamol inj 300mg

paracetamol inj 600mg

Aseptic Processing

The filling environment, equipment, containers and personnel are sterilized to produce a sterile drug product:

• Primary packaging components are sterilized off-line by autoclaving.

• Solutions are sterile filtered into pre-sterilized holding tanks.

• The filling room is maintained at positive pressure and proper air classifications.

• Filling needles are sanitized with steam between fills to maintain sterility.

• Line clearance procedures are followed when changing between products.

Proper aseptic techniques ensure liquid injections remain sterile during filling and long-term storage. Validation and controls are implemented to prove the efficacy of the aseptic process.

Pharmaceutical liquid injections Sterilization

Sterilization is a critical step in pharmaceutical liquid injection manufacturing to ensure the final product is free of viable microorganisms. There are several methods of terminal sterilization used for pharmaceutical injections:

Heat:

• Steam sterilization (autoclaving) - One of the most common methods, it uses saturated steam under pressure. The autoclave is heated to 121°C to achieve sterilization. The high temperature provides efficient microorganism inactivation. However, the process may have an impact on heat sensitive APIs or excipients.

• Dry heat sterilization - An oven-like device is heated to 140-170°C without moisture. It provides a longer sterilization time but is less damaging than moist heat. Dry heat works by oxidation and protein denaturation. It is only used for products able to withstand the temperature and moisture loss.

Radiation:

• Gamma irradiation - This method uses ionizing energy from a cobalt-60 or cesium-137 source. It penetrates packaging to sterilize the contents. Gamma irradiation offers high efficacy but can negatively impact APIs and excipients that are radiation sensitive.

•Electron beam processing - An electron particle accelerator is used to treat products with a measured dose of ionizing radiation for microbial inactivation. It provides high penetration and fast treatment time. However, electron beams have lower penetration than gamma rays.

Pharmaceutical liquid injections Packaging

Packaging is a critical step in pharmaceutical liquid injection manufacturing to ensure sterility and stability. The primary packaging components are:

Vial Materials:

Vials for injections are typically made of glass. Glass provides an inert container that will not interact with the drug product. The most common glasses used are USP Type I treated borosilicate glass or USP Type II treated soda lime glass. These glasses have enhanced chemical resistances to alkalis and acids. The vial glass must meet compendial requirements for containers specified in the US Pharmacopoeia and European Pharmacopoeia.

Glass vials are available in different standard sizes ranging from 1 mL to 100 mL. The glass can be molded into different shapes such as round, rectangular, or oval. The glass color is usually clear for visibility of the injectable solution, but amber glass can be used to protect light-sensitive drug products.

Plastic vials are also an option, but less common than glass due to potential drug compatibility issues. The most common plastics are polypropylene and cyclic olefin polymer.

Capping:

Vial caps ensure the injectable remains sterile. The main cap types are:

• Aluminum caps - Most common. Crimped onto the vial to create a seal. Available with flip-off tops.

• Rubber stoppers - Provide a tight seal and allow needle insertion for withdrawal of the injectable. Made of synthetic rubber such as bromobutyl.

• Plastic caps - Used with plastic vials. Can have flip-off tops or allow for needle insertion.

Labeling:

Vial labeling provides important information for patient safety. The label identifies:

• Drug name and dosage amount

• Manufacturer information

• Lot number and expiration date

• Administration instructions

• Warning labels

The labeling must meet regulatory requirements of the target market. Labeling is applied to vials after filling and sterilization steps.

Testing:

Quality control testing is a crucial part of pharmaceutical liquid injection manufacturing. This testing ensures that each batch meets the required quality standards for safety and efficacy.

Sterility testing confirms that the final product is free of microbial contamination. Samples from each batch are incubated in growth media to detect any microbial growth. The sterility test method must comply with pharmacopeia standards such as USP or EP.

Additional quality control tests may include:

• Appearance - inspecting against visible contaminants.

• pH testing - ensuring the pH is within the specified range.

• Extractable volume - verifying the correct amount can be extracted.

• Particulate matter - detecting and counting particles above a certain size.

• Endotoxin - testing for pyrogens using the bacterial endotoxin test.

• Potency - verifying the drug substance is within potency limits.

• Container integrity - ensuring proper seal and absence of defects.

Comprehensive quality control testing provides assurance to patients that the medicine is safe for injection. Pharmaceutical companies are required to have quality control laboratories to perform release testing on every batch prior to distribution. Proper testing protocols and documentation are critical for regulatory compliance.

Regulations

The pharmaceutical industry is highly regulated to ensure the safety, efficacy, and quality of liquid injectable products. Key regulations include:

Good Manufacturing Practices (GMPs)

GMPs provide a framework for ensuring pharmaceutical quality through all stages of manufacturing. GMP regulations cover:

• Personnel training and hygiene.

• Facility and equipment design, maintenance and cleaning.

• Material handling and storage.

• Production processes and quality control.

• Packaging, labeling and distribution.

• Record keeping and documentation.

GMPs require robust quality systems, standard operating procedures (SOPs), and stringent change control. Facilities must be routinely audited by regulators.

Regulatory Guidelines

In addition to GMPs, there are specific regulatory guidelines pertaining to sterile injectable manufacturing, such as:

• Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice (FDA guidance).

• Annex 1: Manufacture of Sterile Medicinal Products (EU GMP).

• Sterile Production and Quality Control (WHO recommendations).

These provide further expectations around facility design, equipment, personnel behaviors, cleaning and disinfection, component and product sterilization, aseptic processing, and environmental and product monitoring.

Adhering to GMPs and regulatory guidelines ensures injectable drugs meet required quality standards. Companies must routinely inspect their own operations and be prepared for regulatory inspections. Full compliance is essential.