Sterile Manufacturing | Injectables & Parenterals

Overview of sterile manufacturing contract services for parenteral preparations, sterile injectables & lyophilized products offered by CDMOs & CMOs.

Q1. What are parenteral preparations?

Parenteral preparations are sterile preparations containing one or more active ingredients intended for administration by injection, infusion or implantation into the body. They are packaged in either single-dose or multidose containers.

Parenteral preparations may also be defined as solutions, suspensions, emulsions for injection or infusion, sterile powders for injection or infusion, and gels for injection and implantation that enter systemic circulation and typically provide rapid onset of action in comparison to orally administered drug products.

There are various CDMOs and CMOs offering contract manufacturing for parenteral formulations. Furthermore, parenterals are drug products that reach the body by circumventing the gastrointestinal tract, including liquid drug products.

Parenteral Drug Delivery - Routes of Administration:

* Intravenous

* Intramuscular

* Subcutaneous

* Intradermal

* Epidural

* Intra-articular

* Intrathecal

Types of parenteral preparations based on physical attributes:

- Solutions or emulsions: Medicaments suitable for injection.

- Sterile solids: Drugs which are not stable as solutions (dry sterile solids dissolved in suitable solvents).

- Sterile suspensions: Suitable solvents administered via the intramuscular route of administration.

- Transfusion fluids: Solutions administered via the intravenous route of drug delivery.

Types of Parenteral Preparations based on Volume:

-Small Volume Parenterals

Sterile pyrogen free preparations intended to be delivered via a parenteral drug delivery route, supplied in single or multiple doses. Its volume is generally less than or equal to 100 ml and often ranges from 1-30 ml. Small-volume parenteral products are often presented in vials or ready-to-use pre-filled syringes, providing ease-of-use in the clinical setting or for patient self-administration.

-Large Volume Parenterals

Sterile preparations containing active ingredients mostly supplied in a single dose of more than 100 ml. Large volume parenterals are delivered through the intravenous route of administration. They generally provide electrolytes and nutrition to the body.

Advantages of parenteral preparations as compared to other dosage forms:

- Faster onset of action

- Drugs that can’t be delivered orally may be delivered by the parenteral route of administration

- Improve adherence

- Enable administration to patients who are unconscious or otherwise unable to receive medication

- Control over drug delivery

- Parenteral administration can result in local effect for drugs when desired

- Parenteral therapeutics provide a means of correcting serious disturbances of fluid and electronic balances

- The drug action can be prolonged by modifying the formulation.

- Easy to formulate

- Uniform doses

Q2. What are the considerations involved in developing complex parenteral formulations?

Complex parenteral formulation or drug product challenges classically pertain to the attainment of a target physicochemical characteristic, eg, active concentration/drug loading or particle size distribution.

Like simple formulations, complex formulations must be formulated to be safe, stable, and effective in the target patient population. They must align with regulatory expectations and be manufactured under strict aseptic control. Yet compliance with rigid guidelines is a challenge that continues to elude companies offering sterile contract manufacturing for parenteral formulations worldwide.

Developing different complex parenteral formulations depends on a number of factors including desired route of administration, area of administration, onset of action, rate of drug release, shelf life, etc. Some additional general considerations which are paramount for developing parenteral dosage forms, are noted below.

- Stability: All products must be stable, not only chemically and physically like all other dosage forms, but also ‘stable’ microbiologically. This further helps parenteral preparations to have longer shelf lives and assures safety and potency to consumers.

- Sterility: All parenteral products must be sterile. This is of paramount importance as these products are administered directly into the bloodstream, bypassing the body’s natural defenses. Contamination of parenteral drug products, therefore, can have serious consequences on the patient.

- Apyrogenicity (Chemical purity): All parenteral preparations must be free from endotoxin contamination. The most important type of pyrogen in pharmaceutical fields is bacterial endotoxin, which, if present in a parenteral pharmaceutical, can result in a pyrogenic response (chills, fever, headache, myalgia, malaise) by the consumer.

- Isotonicity: Products should be isotonic, although strictness of tonicity depends on the route of administration. It is important because isotonicity reduces the chances of hemolysis, the possibility that the parenteral preparation may penetrate red blood cells.

- Excipient Selection: Selecting suitable excipients during the preliminary stages of drug product development and manufacturing is crucial. It is also important in case of parenteral development. Parenteral preparations need careful planning and thorough knowledge of medicaments and adjuvants to be used. The excess use of adjuvants in parenteral products should be avoided as some of these may interfere with the drug.

- Commercial Production: Parenteral development chemistries must serve commercial and sterile manufacturing interests as formulation has direct influence on scale-up and process variability, stability and other processing, and manufacturing-oriented aspects related to successful commercial drug product development and manufacturing.

There are copious other considerations taken into account prior to commencing parenteral contract manufacturing or contract manufacturing of injectables. This enables the production of superior products that elicit the desired therapeutic effects upon administration in a convenient and timely manner. Services for contract manufacturing of injectables and contract manufacturing for parenteral formulations are offered by various CDMOs and CMOs.

Q3. What are the steps involved in manufacturing sterile injectables?

Injections are sterile solutions or suspensions of drug products in an aqueous or oily vehicle meant for introduction into the body by means of an injectable needle, under or through one or more layers of the skin or mucous membrane.

Only liquid dosage forms can be injected which means that parenteral preparations must either be a liquid which can itself be injected safely, or it may be a material that can be diluted with sterile water or other sterile solvents before it is administered.

Parenteral preparations may require the use of excipients such as solvents, substances to enhance solubility, suspending agents,buffering agents, substances to make the preparation isotonic with blood, stabilizers or antimicrobial preservatives. In general, there are two ways of manufacturing sterile injectables or sterile drug products; (1) Terminal Sterilization and (2) Aseptic Sterile Manufacturing.

Contract Manufacturing of Injectables - Methods:

(I) Terminal Sterilization

Terminal sterilization is the process of sterilizing a product in its final container. It is an important process as it ensures the product remains sterile. All medical, ophthalmic and parenteral equipment are sterilized in batches, and are usually sterilized using heat.

(II) Aseptic Sterile Manufacturing and Sterile Fill-Finish

Aseptic filling of sterile drugs, also known as sterile fill finish, remains one of the most critical processes in pharmaceutical sterile manufacturing. This is due to its highly technique driven processes and the potential safety impact to the end user, usually an already compromised patient.

General steps involved in manufacturing sterile injectable dosage forms:

I. Pre-formulation & Formulation Studies

The first step of manufacturing sterile injectables is performing extensive pre formulation studies for identifying physical attributes (pH stability, thermal stability, etc.) of potential drug formulations and formulation studies to identify requirements of certain excipients (surfactant, stabilizer, etc.). Subsequently, a suitable drug candidate and compatible excipients are chosen to constitute the final drug formulation.

II. Process Compatibility

The next step includes learning how the formulation behaves/interacts in an aseptic manufacturing facility when it comes into contact with different materials, enumerated below. Process optimization is achieved after analyzing the results of such studies.

1. Glass

2. Stainless steel

3. Process tubing

4. Plastics

- Other Materials

III. Compounding/Mixing

The chosen raw materials then undergo the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient. Compounding involves combining two or more drugs.

IV. Filtration

Filtration through a membrane and/or filtering processes using compressed gas and air are used in parenteral contract manufacturing or sterile injectable contract manufacturing, to remove unwanted materials from the formulated bulk solution.

V. Filling

Once the product has been filtered into a sterile filling container and the filter passes the postfill integrity test, it is now ready to fill into its primary container. The product is generally filled into glass vials; however, different types of containers can be used for filling depending on the product.

VI. Terminal Sterilization

Parenteral products must undergo some form of sterilization, and terminal sterilization is generally the preferred method. Terminal sterilization is the preferred method for drug products because, in this process, sterilization takes place after the product has been filled into the primary packaging. Because of this, there are no further opportunities for contamination due to human intervention.

VII. Lyophilization

Contract manufacturing of lyophilized injections is achieved via lyophilization. Lyophilization is the removal of water from frozen state to the gaseous state without going into the liquid state. In lyophilization of parenterals, the drug is dissolved in an appropriate solvent and converted to ice form at a very low temperature between ?50 °C and ?90 °C.

VIII. Closing/Stopping

Pre-sterilized stoppers and caps are then used to seal the containers filled with the sterilized and lyophilized drug formulations or lyophilized products.

IX. Inspection

After the product is released following QA & QC testing, inspections of the physical attributes of the drug products and containers are performed prior to labeling.

X. Labeling

Sophisticated label solutions can play an important role in supporting product and patient safety. Labels serve to clearly and reliably mark the pharmaceutical product by providing information on the product, its administration, batch number, expiry date, etc.

XI. Packaging

Secondary packaging is then carried out to prepare the parenteral formulations for large-scale distribution and commercialization.

Q4. How are lyophilized injections a boon to injectable dosage forms?

Lyophilization is a water removal process through which perishable items are preserved. Lyophilization is the process of preserving something by freezing it very quickly and then subjecting it to a vacuum which removes ice.

Lyophilization is one of the most effective methods for the long-term preservation of cells. Freeze drying, known as lyophilization, may be used to prepare a dosage form that is to be reconstituted for injections. This process boosts the shelf life of the material and also makes it easier to transport by injectable and parenteral CDMOs or CMOs offering contract manufacturing services for sterile injectables.

Lyophilization: Three stages

I. Freezing

The first and most critical stage of lyophilization is the freezing phase. There are various methods to freeze the product. Freezing can be done in a freezer, a chilled bath (shell freezer) or on a shelf in the freeze dryer. Cooling the material below its triple point ensures that sublimation, rather than melting, will occur.

II. Primary drying

Primary drying, the sublimation stage, is the process of converting ice directly into a gas without melting. The product is held at a temperature lower than the eutectoid of the ice and controlled vacuum conditions are used to remove the vapour.

III. Secondary drying

Secondary drying (adsorption) removes the bound water molecules. The temperature is slowly raised to higher than that in the primary drying phase. Bonds are broken between the material and the bound water molecules. The temperature for this process is usually between 10°C and 50°C and usually requires a long duration.

Lyophilized injections are the best alternative to oral solid dosage forms. After contract manufacturing for lyophilized injections is performed, they are packed in lyophilized vials. Lyophilized injections provide better patient compliance, especially in bed ridden patients.

Now-a-days,there are many CDMOs offering contract manufacturing for lyophilized injections. Lyophilized injection dosage forms are extensively used to improve the bioavailability, stability, solubility of injectable formulations. Lyophilized injections are prescribed to attain maximum bioavailability and stability in patients suffering from a number of diseases.

Other advantages of lyophilization and lyophilized products include:

- Ease of processing a liquid, which simplifies aseptic handling

- Enhanced stability of a dry sterile powder

- Removal of water without excessive heating of the product

- Enhanced product stability in a dry state

- Rapid and easy dissolution of reconstituted product

- Increased shelf life

- Reduce weight and volume for better transportation

- Avoids sample shrinking

Q5. Who are the leading contract manufacturers for injectable formulations?

Some of the leading injectable and parenteral CDMOs and CMOs offering sterile contract manufacturing services for parenteral or injectable dosage forms include:

Madras Pharmaceuticals

Steril-Gene Life Sciences, a joint venture between the Madras Pharma Group and Lloyd Laboratories, a pharmaceutical CMO, offers sterile injectable contract manufacturing services for a range of pharmaceutical preparations like tablets, softgel capsules, general injections, lyophilized injections (lyophilized products), etc. They also have injection block facilities for liquid injections in ampoules, vials and lyophilized vials.

Bioindustria L.I.M. Spa

Bioindustria Laboratorio Italiano Medicinali L.I.M. S.p.A. has a long tradition in the pharmaceutical business and specializes in large and small volume injectables with terminal sterilization or with aseptic process, lyophilised dosage forms in lyophilized vials , tablets and capsules. They provide contract manufacturing for lyophilized injections and also offer sterile injectable contract manufacturing (parenteral contract manufacturing services).

Quotient Sciences

Quotient Sciences provides enhanced d formulation decision-making in early phase clinical trials for parenteral products. They follow a GMP compliant approach and offer contract manufacturing for parenteral formulations for rapid clinical assessment.

They provide parenteral quality control services and programs to optimize parenteral formulations. Furthermore, Quotient Sciences also offers high-potency API contract manufacturing of injectables.

Recipharm AB

Recipharm, a pharmaceutical injectable and parenteral CDMO, develops injectable dosage forms for clinical trials as well as for market launch. They have the competence to work with all types of parenteral products such as those delivered via the intravenous, intramuscular and subcutaneous routes of administration.

Their drug product development and manufacturing (parenteral development) team has experience with essentially all types of parenteral formulations and provide solutions, dispersed systems and sterile powder formulations. They have dedicated facilities to manufacture smaller batches of clinical trial material and commercial manufacturing sites for larger clinical batches.

Biopharma

Biopharma, an FDA approved CMO for beta lactam antibiotics finished drug products, has a wide and global experience in contract manufacturing for parenteral formulations. Apart from contract manufacturing of injectables, they also produce various oral dosage forms.

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