Parenteral Drugs: Formulation Requirements and Common Challenges

When we think about medication, the first thought in our minds is a pill. That’s because pills, tablets, and capsules, or as they’re called in the pharmaceutical world—oral doses—are the most common method of administering medication. However, medication can be administered via another route: parenteral drug administration. 

In this blog, Pharma Now discusses Parenteral Drugs, their formulation requirements, common challenges and solutions. Keep reading to learn more. 

What are Parenteral Drugs?

Parenteral drugs are administered directly into the human body using injections. This direct administration ensures rapid adsorption of the medication, and this administration route is often used for patients who cannot consume oral medications for medical reasons. In essence, parenteral drugs can be injected into the bloodstream (intravenous), muscle tissues (intramuscular), under the skin (subcutaneous and intradermal) or to specific areas (e.g., spinal cord, joints, eye, etc.).

As parenteral drugs are directly injected into the bloodstream, they bypass the human body’s natural defence mechanisms. Therefore, any issues in parenteral drug formulations can directly and severely affect the patient’s health. Consequently, these drugs have strict formulation requirements.

Formulation Requirements of Parenteral Drugs

While formulating parenteral drugs, manufacturers must adhere to strict guidelines regarding several criteria. This includes:

High-purity water must be used.

All manufacturing processes use only high-purity water with no traces of bacteria or other microorganisms. Many manufacturers source high-purity water from third-party sources and still purify it using in-house purification systems. Such strict protocols are necessary because water may contain bacterial endotoxins that can cause severe reactions.

Isotonicity must be confirmed.

Isotonicity refers to the process of ensuring the concentration of water and solutes in a solution is the same as in another solution. In the context of parenteral drugs, manufacturers have to ensure the final formulation has the same osmolarity as the body fluid. The formulation’s osmolarity is adjusted using sodium chloride, dextrose and similar human-safe osmotic agents. If the osmolarity is not the same, it can result in cell damage, pain or irritation at the injection site.

The formulation’s pH must match.

The pH of the parenteral drug is also strictly controlled to ensure the drug is compatible with the human body’s physiological conditions. Extreme pH levels (both high and low) can result in irritation or pain and—in the worst scenarios—destabilization of the drug. Often, the pH of the formulation is adjusted using buffers.

They must be manufactured in a sterile and pyrogen-free environment.

The final parenteral formulation must be 100% free of microorganisms and contaminants to ensure it does not face any unwanted side effects. Hence, parenteral drugs are strictly manufactured in cleanrooms where all environmental factors (e.g., temperature, humidity, particulate matter content, microorganisms, etc.) can be strictly controlled.

It should have good solubility.

The solubility of the drug in body fluids is also strictly controlled. If the formulation is injected but is not soluble in the body, it may not work or may have adverse effects. Hence, the solubility of parenteral formulations is tuned using surfactants and stabilizers.

It should demonstrate excellent stability.

The parenteral drug formulation must remain stable under physiological conditions for the maximum effect. Hence, its stability against common physiological processes in the human body (e.g., hydrolysis, oxidation, and aggregation) is also studied and adjusted. Stabilizers, chelating agents, and antioxidants are added to ensure the formulation demonstrates the required stability.

Additionally, its stability in delivery systems (e.g., vials, syringes, and IV bags) is also studied to make sure the drug does not degrade before reaching the patient.

It should be biocompatible.

Finally, and most importantly, the formulation must be biocompatible. It should not cause any adverse reactions, such as irritation and should not be toxic to tissues and blood vessels. The formulation’s absorption and bioavailability after injection are thoroughly studied to ensure it releases and acts in a desired manner. Manufacturers must create and adhere to strict guidelines to ensure the final formulation is safe for patients. In addition, they also have to adhere to good manufacturing practices (GMP). Sticking to so many requirements is challenging, and according to many experts, the parenteral drug formulations face more challenges than other formulations.

Common Challenges in Parenteral Drug Formulations

Because the formulation requirements for parenteral drug formulations are so rigid, there is almost no room for error, which is understandable because poor parenteral drug formulations can have permanent adverse effects and death. Consequently, pharma manufacturers often face several common challenges in parenteral drug formulations.

Stringent regulatory guidelines

According to the experts, parenteral drug formulations are subject to stricter regulatory requirements than other formulations because of their fast-acting nature. Regulatory bodies often provide very narrow deviation ranges for all parameters, such as endotoxin limits, to ensure patient safety, and pharma manufacturers have to ensure all dosages fall within these ranges to obtain approval.

Exhaustive investments

Parenteral drug formulations need to be manufactured under strictly sterile, contaminant-free, and pyrogen-free conditions. Hence, pharmaceutical companies have to make exhaustive investments to purchase equipment that meets the standards. Furthermore, maintenance and upgrading of the equipment to maintain efficiency is just as expensive.

Difficult scalability

Considering the comprehensive set-up required for parenteral drugs, scaling up manufacturing to meet demand is also challenging. Specialized equipment needs to be integrated, and existing units that have been used to manufacture other formulations cannot be directly used, which further increases the costs associated with manufacturing parenteral drugs.

Stability and shelf-life concerns

Parenteral drugs, especially biologics, have a tendency to degrade. Maintaining their stability is challenging because all environmental factors, including temperature, pH, humidity and light, need to be controlled to prevent degradation. After manufacturing, cold-chain logistics needs to be employed to ensure the drugs remain stable during transport and storage.

Formulation issues

In addition to stability, the formulation also faces other challenges, such as poor solubility, poor biocompatibility with both the human body and delivery systems, low bioavailability, and side reactions at injection sites. These issues need to be solved while ensuring the other requirements are met, which is particularly challenging because there are very narrow deviation ranges for each parameter.

These challenges persist across all pharmaceutical companies, making manufacturing of parenteral drugs expensive, time-consuming, and not worthwhile. Consequently, many pharma manufacturers outsource the manufacturing of parenteral formulations to contract manufacturers to reduce their financial burden.

Unique solutions to solve problems!

Here are some solutions pharma manufacturers and contract manufacturing organizations implemented to address the common challenges in parenteral drug manufacturing:



Advanced sterilization and contamination control systems

Pharma manufacturers have integrated closed aseptic manufacturing systems and next-gen sterilization systems to control environmental factors in clean rooms. These systems have various sterilization options like supercritical CO2, electron beam, and vapour-phase hydrogen peroxide sterilization.

Smart endotoxin detection and removal systems

These systems use microfluidic biosensors and affinity chromatography techniques for the detection and removal of endotoxins from formulations in real-time. The use of these techniques reduces the processing time.

Nanotechnology-based drug stabilization

Nanomaterials like liposomes, micelles, and dendrimers are used as carriers for parenteral drug formulations. These carriers prevent the degradation of the formulation and increase its shelf-life. They also increase the solubility of the formulation and reduce the chances of side reactions at the injection site.

Conclusion

Parenteral formulations are an important class of medications used to treat serious diseases and conditions. Due to their sensitivity, their manufacturing is challenging and strictly regulated. Pharma companies often have to use specialized equipment to ensure the formulation does not deviate from the desired quality. 

However, doing so poses many challenges, the most important of which are regulatory hurdles and financial constraints. While several developments have overcome manufacturing limitations, pharma companies must tackle many more. Thankfully, as technologies rapidly advance, we can expect new solutions to these challenges in the near future.

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FAQs

1. What happens if a parenteral drug formulation has poor quality?

A parenteral formulation with poor quality can result in mild side effects such as skin irritation or even death because the formulation bypasses the natural defenses in the human body.

2. When is parenteral administration used?

Parenteral formulations are used when rapid effect or precis dose delivery is desired. They are also used if the formulation is incompatible with the gastrointestinal tract or if the patient cannot consume oral formulations due to medical reasons.

3. Why do pharma manufacturers outsource parenteral drug manufacturing?

Parenteral drug manufacturing has strict manufacturing requirements, and implementing these is financially challenging or impossible for many companies. Hence, the manufacturing process is outsourced to contract manufacturing organizations.