Challenges for Powders for injection (PIs)

Powders for injection (PIs) are a popular parenteral dosage form for drugs (active molecules). Because of their instability in the aqueous environment, PIs cannot be marketed as ready-to-use injectables. Instead, they are marketed as dry powders to be reconstituted with a suitable vehicle just before administration. The final form after reconstitution may be either a solution or a suspension. Typical molecules in this category include ß-lactam antibiotics, cephalosporins, and acyclovir. A few ready-to-use infusion products are marketed as frozen solutions in plastic bags for these molecules. However, the low temperature required for their shipment and storage makes these products an unviable option, especially in countries in which a cold chain from manufacturing to the point of consumption is difficult to establish. PIs are relatively simple with respect to formulation and process development. However, their performance and stability are critically affected by a number of parameters. The development of a successful powder for injection formulation requires careful study of preformulation parameters, packaging and process parameters, and the elimination of particulate matter.

Throughout manufacturing certain procedures should be validated and monitored by carrying out appropriate in-process controls. These should be designed to guarantee the effectiveness of each stage of production. In-process controls during manufacture of powder for injection should include monitoring of environmental conditions (especially with respect to particulate and microbial contamination), bacterial endotoxins, pH and clarity of solution, free from particulate matter and integrity of the container-closure system (absence of leakage, etc.). For powders for injections controls should also include uniformity of mass, moisture content and the ease of reconstitution of a solution or suspension. The validation of the manufacturing process and the in-process controls are documented.

Reconstitution:

Typically, PI drugs are supplied in glass vials with rubber plugs and are mixed or reconstituted with a diluent. An incompletely dissolved product can be hazardous to the patient, thereby making reconstitution a critical performance parameter for these products. Variability in the reconstitution time of a product from the same or different manufacturers can seriously affect patient safety. The mention of a specific reconstitution time in the product literature or label could ensure a reproducible performance of the product in terms of complete reconstitution. Few USP monographs of PIs specify the reconstitution time. Therefore, special inputs from formulation scientists are required to optimize the reconstitution time during the development of these dosage forms. Keeping in mind the importance of reconstitution, the knowledge of parameters affecting reconstitution time is critical for product development, quality control, and overall product performance. Particulate matter in dry powder injectables remains a primary area of concern. Various investigative reports in the literature have addressed this important issue. The problem of particulate matter in PIs assumes greater significance because no active approach such as filtration can be applied during the manufacturing stage. However, judicious application of preventive approaches can help achieve desired standards of particulate matter. All possibilities should be carefully evaluated because many times, multiple factors might be contributing to the problem.

Particle size:

The particle size of the drug can affect the PIs formulation by modifying the dissolution rate and time required for reconstitution and by influencing the syringeability of the suspension. Particle size also affects the level of pain at the site of injection with suspensions. The particle-size distribution should be controlled at the sterile bulk drug manufacturing facility. Attempts to modify particle-size distribution by milling and sieving could seriously affect sterility and levels of particulate matter. Therefore, pharmaceutical preformulation scientists should establish the specifications for particle-size distribution that must be met by the bulk drug manufacturer.

Environmental condition:

Environmental condition monitoring of manufacturing area is critical process parameter for process validation. In environmental monitoring critical parameter like, temperature, relative humidity, and differential pressure, viable or non-viable particles are generally monitored. Relative humidity and temperature play a significant role in pharmaceutical manufacturing, and it is a critical parameter in powders for injection manufacturing. It is very important to check the relative humidity    and temperature of the filling room to avoid any quality issues with the product. The injectable dry filling area is a completely sterile area of the company that is a strictly controlled area. The high-level alertness is mandatory to maintain the atmospheric condition in the filling area of the dry powder filling area of Injectable. Every step in the production area requires a written SOP.

Moisture:

Moisture remains to be a great risk to the pharmaceutical industry. Moisture is known to cause deterioration of hygroscopic substances; it activates reaction between containers and the pharmaceutical substances in them and it is also known to cause solidification of dry powder injection.

Stability of the reconstituted solution or suspension:

The following parameters must be evaluated during the course of accelerated and real-time stability studies:

• Assay and related substances (dry powder and reconstituted suspension)Water content
• Discoloration (colour absorbance value)
• pH of the reconstituted solution
• pH of the reconstituted product
• Reconstitution time
• Clarity of the reconstituted solution (particulate matter)
• Sterility
• Bacterial Endotoxins 

Training:

Training is an essential aspect of good manufacturing practices (GMP) in the pharmaceutical industry. Training and retraining are one of the foundational core activities that regulatory agencies often review during inspections to ensure that ongoing training is provided to key personnel so that they can demonstrate process knowledge and their ability to adhere to routine standard operating procedures. Control systems for robotics are complex systems, and training is crucial for operating and maintaining these systems. Automation and control are key to successful implementation of robotics, including the understanding of the mechanics and electronics involved in making the robots function as intended.

Conclusion: 

PIs are relatively simple formulations with regard to the number of excipients and the manufacturing process. Development of a successful formulation requires careful study of preformulation parameters, especially those related to solid-state pharmaceutics. By acting at the molecular, particle, bulk levels, environmental condition, these parameters affect both the fundamental and derived properties of a bulk drug. In addition, contribution of packaging and process parameters to overall product stability must be carefully considered. Particulate matter in PIs is a common and troublesome issue. A stepwise approach giving due consideration to all contributing factors can help limit the particulate matter within specified limits. A multidimensional approach involving preformulation, formulation development, packaging development, process optimization, and environmental control will ensure the development of a stable PIs formulation.

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About the Author:

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”.

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