Considerations in Development and Manufacturing of Complex Injectables for Early Phase Studies

Overview

A complex injectable has an active ingredient, formulation, delivery route, or drug device combinations that are complicated. Despite these challenges, complex injectables have gained increasing attention due to their advantage in applications in acute and chronic diseases treatments.

Complex parenteral products are in multiple delivery systems. Sterile suspensions, liposomes, lipid nanoparticles, emulsions, polymeric microspheres, and pellet implants are used to administer a drug via injection, ophthalmic, subcutaneous, or implant route.

In particular, suspensions and lipid-based nanoparticles are increasingly utilized. The reason is their ability to increase drug loading to improve bioavailability/stability and to enable long-acting injectable of poorly soluble drugs and biologicals.

Injectables are extremely complicated to develop and manufacture. Careful design of formulation and process, in-depth characterization of products, confirmation of safety and efficacy per FDA regulation, and high-quality standards in manufacturing, packaging, distribution, and storage are all required.

Production of the first clinical trial materials for a new pharmaceutical dosage form is a significant milestone in pharmaceutical product development. As a product transitions from pre-clinical to the clinical phase, the manufacturing process takes on a much greater role in overall project success.

This transition is particularly difficult for emerging pharmaceutical companies whose expertise typically lies in the biology and chemistry, and less on the engineering, regulatory, and quality aspects of manufacturing. Achieving this critical milestone is made even more daunting when the drug product is intended to be a sterile injectable dosage form.

Development of Complex Injectable Dosage Forms

Suspensions/Nanosuspensions

Physical stability is the primary consideration for suspensions; they tend to settle over time and particle size distribution changes. Physical stability in suspensions can be controlled in three ways:

(1) Adding flocculating agents to enhance particle “dispersability.” The addition of the flocculating agent, at some critical concentration, negates the surface charge on the suspended particles and allows the formation of floccules (particle clusters) that are held loosely together by weak van der Waals forces. Because of how they are linked, they will not cake and may be easily re-dispersed by shaking the suspension.

(2) Adding viscosity enhancers to reduce the sedimentation rate in the flocculated suspension.  Viscosity enhancers are typically hydrocolloids used in a concentration that overcomes the suspended particle’s tendency to settle.

(3) Selecting appropriate stabilizer and surfactant.

Preparing parenteral suspensions can be done a few ways. One is aseptically combining sterile powder and vehicle. It involves aseptically dispersing the sterile, milled active ingredient(s) into a sterile vehicle system. Next, the resulting suspension is aseptically milled as required. Lastly, the milled suspension is aseptically filled into suitable containers.

Another method is in-situ crystal formation by combining sterile solutions. Active ingredient(s) are solubilized in a suitable solvent system. A sterile vehicle system or counter solvent is added, causing the active ingredient to crystallize. The organic solvent is aseptically removed, with the resulting suspension aseptically milled, as necessary, and then filled into suitable containers. Sterility is achieved by an aseptic process or a terminal sterilization, if those suspensions have enough thermal or irradiation stability upon the sterilization process.

Lipid-based Nanoparticles

Lipid-based nanoparticles, such as lipid complexes, lipid nanoparticles, and liposomes, are formed from lipids and other excipients in aqueous medium. Lipid nanoparticles can be produced by dispersion of lipids in water via mechanic energy. Lipid nanoparticles are formed as a result. Further extrusion may be utilized to refine the particle size distribution to a narrower range. Lipid nanoparticles can entrap hydrophilic and hydrophobic drugs, and drug release can be targeted to specific sites.

Typically, lipid nanoparticles range in size from 50 nm to 200 nm. To make them suitable for therapeutic applications, their size distribution must be controlled. For lipid nanoparticles to be processed by 0.22-micron sterile filtration, its particle size distribution has to be well below 200 nm; otherwise, an aseptic process needs to be utilized.

Emulsions/Microemulsions

You can characterize emulsions as macroemulsions, microemulsions, or nanoemulsions.

Macroemulsions are usually opaque due to the average particle size of the hydrophobic droplet is typically > 500 nm and thus scatters light.

Microemulsions and nanoemulsions are obtained when the size of the droplet is typically <500 nm. Microemulsions are thermodynamically stable due to the use of sufficient co-solvents and co-surfactants to prevent Ostwald ripening. Nanoemulsions contain much less of the stabilizing co-solvents and co-surfactants. The result is they are meta-stable and more susceptible to Ostwald ripening.

The emulsion can be prepared via high- and low-energy processes. A high-energy method includes high-pressure homogenization, micro-fluidization, and ultrasonication normally used to make emulsions. Low-energy methods are utilized to prepare microemulsions. Terminal sterilization will be used if the emulsion has good thermal stability, otherwise aseptic process or filter sterilization will have to be exploited. To enable 0.22-micron sterile filtration, emulsion particles size distribution must to be below 200 nm, and its viscosity should be low enough so formulation can flow freely through the filtration membrane.

Polymeric Nano/Microparticles

To realize long-acting attributes, the polymeric macro/nanoparticles can protect the drug from burst release and degradation, thus achieving prolonged drug delivery and a longer shelf-life. For therapeutic purposes, the most commonly used polymers include polyethylene glycol (PEG), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), alginate, chitosan, and gelatin base.

Polymeric microspheres can be developed based on hydrophobic materials that facilitate controlled release of the therapeutic. This is achieved via slow degradation of the microsphere’s polymer backbone that subsequently leads to kinetically driven release of the drug. Long-established polymer microspheres that have had significant success are based on incorporation of leuprolide into polylactide (PLA) and polylactide-co-glycolic acid (PLGA) microspheres. Sterility of polymeric microparticles can be achieved via aseptic process or terminal sterilization, if the product has ample thermal or irradiation stability upon the sterilization process.

GMP Considerations  

Regulatory Requirements

An amended rule that applies to small molecule drugs and biologics became effective by the FDA on September 15, 2008. The note in the Federal Register of July 15, 2008 (Volume 73, No. 136) announced an adaptation of 21 CFR 210 and 211: investigational medicinal products solely intended for use in Phase 1 are to be exempted from complying with the “final rule” under FD&C Act 505(i) (21 U.S.C 355(i)). The text stresses that the cGMP requirements of 21 CFR 211 are applicable only to Phase 2 and Phase 3 drugs. A solid rationale for Phase 1 clinical trials production to focus on safety of manufacture rather than qualification of processes is established by this rule.

Sterility and non-pyrogenicity are of utmost importance for Phase 1 sterile manufacture, too. The injectable product can be terminally sterilized in its packaging or manufactured aseptically. Aseptic manufacturing of sterile products is only acceptable if all methods of terminal sterilization in the final sealed container fail. In the U.S., the FDA’s 2004 publication Guidance for Industry Sterile Drug Products Produced by Aseptic Processing details  the expectations of the FDA for the validation of aseptic processing.

Facility, Environment and Equipment

The amount of the drug substance available is often very small in early phase trials. Matching the equipment scale and material handling expertise with the product batch size is essential to ensure a successful, cost-effective outcome. Fill and finish contract manufacturing organizations (CMOs) that manufacture high-volume commercial products typically lack the equipment and personnel to manage a developing product that requires low-volume and flexibility in scheduling.

Companies that specialize in small-volume early stage products have staff experience in rapid small-scale manufacturing campaigns. A smaller support staff generally has greater flexibility with regard to changes and timing. The lead time for changes at a smaller contract development and manufacturing organization (CDMO) should be less than larger CMOs. Large CMOs have much greater capacity but tend to be more rigid and generally have defined systems in place that are not easily changed and longer lead time.

The environment where aseptic processing occurs may require class 100 cleanroom suites, laminar flow hoods, biosafety cabinets, isolators, and a restricted access barrier system (RABS). It is important to have suitable air flow during compounding and manufacturing. All of the air delivered to a cleanroom should pass through HEPA filters. The aseptic process should also include environmental monitoring to ensure microbiological control over the product.

Equipment for the sterilization has to be monitored with calibrated temperature probes and sterilization cycles that are documented and incorporated into the batch record. The product’s contact surface of manufacturing equipment needs cleaning verification following production. Items that cannot be sterilized must be disinfected before entering the cleanrooms. The entire area should be disinfected after processing.

Production Process and Validation

The production process should ensure the sterility and low endotoxin level of the product. If filtration is used as a sterilization method, filters are bubble point tested to ensure integrity. To achieve the aim of a sterile product by an aseptic process, several aspects have to be considered and processes validated. In the end, process simulation with media fill is the key validation measure and allows the final evaluation of the appropriateness of the entire process.

Process validation includes simulation tests using microbial growth media. Validation includes filling of media, environmental monitoring, and incubation and evaluation of the filled vials. Microbial control is an essential element of cGMP for sterile products. Proper aseptic technique, correctly functioning equipment, and adequate cleaning processes are to be demonstrated using media fills. Media fills are conducted routinely to establish that the process, environment, and controls are capable of producing a sterile drug product via an aseptic process.

Quality Control

The Quality Control department is responsible for the release of the finished drug product per specification and review of the manufacturing batch record. It ensures procedures are followed, any investigations are performed, subsequent corrective actions are incorporated, and all testing during the process meets specifications so that the product is demonstrated to be sterile and meets product quality attributes. Micro testing for the finished product includes sterility testing per USP <71>, endotoxin testing per USP <85>, and bioburden testing per USP <61>.

Laboratory Controls

Laboratory tests used in manufacturing should be scientifically sound, suitable, and reliable for the specified purpose. The main purpose of laboratory testing of a Phase 1 investigational drug is to evaluate quality attributes, including identity, strength, potency, and purity. The necessary analytical procedures and methods validation will vary with the IND phase. The main goal of performing “staged” validation in early drug development is to provide test procedures that are reliable, able to support clinical studies, and evaluate the product safety.

Procedures should be written to establish calibration and maintenance procedures for laboratory equipment at appropriate intervals. Personnel verify that the equipment is in good working condition when samples are analyzed (eg, system suitability). A stability study using representative samples of the Phase 1 investigational should be initialized to monitor the stability and quality of the Phase 1 investigational drug during the clinical trial should be performed under ICH temperature, humidity, and light storage conditions.

Personnel and Training

cGMP aseptic techniques should to taught to all personnel involved in the manufacture of clinical trial material. CDMOs should clearly write and follow established procedures throughout the entire manufacturing process.

Personnel are the main source of contamination of cleanrooms with microorganisms. Education and training of the personnel, garments, dress procedures, rules for entry, and behavior inside the cleanrooms are important factors. Detailed standard operating procedures (SOPs) of the CDMO, such as aseptic operation, gowning, room cleaning, as well as personnel and room environmental monitoring procedures, are critical for aseptic manufacturing processes.

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This Formulation Forum was originally published on Drug Development & Delivery.