Fundamentals of Developing Parenteral Drug Products

Advancing to first-in-human clinical trials will require formulation development to design a successful sterile formulation that meets your Target Product Profile (TPP) while being manufacturable, scalable, and robust. In this blog, we discuss the steps and studies involved in formulating effective parenteral medications to ensure that what shines on paper also excels in real-world application.

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What is a Target Product Profile (TPP)?

A target product profile (TPP) is a set of necessary attributes that the final drug product must have for the product to be used. It includes aspects such as pH range, osmolality, and API concentration. The goal of the TPP is to maximize patient comfort while ensuring the drug product remains efficacious. An injection that closely aligns with both the chemical and physical characteristics of the target site in the body minimizes patient discomfort during administration. 

Keep It Simple

As a rule of thumb, the formulation should be kept as simple as possible. The ideal formulation composition would include only the active pharmaceutical ingredient (API) in water and hit the target profile. However, this typically does not happen, in which case excipients are added to achieve the target profile. 

Formulation development is often a balancing act. By addressing one quality aspect of the drug product, it can inadvertently impact another aspect of the formulation. It is important to anticipate ripple effects when changes are made to the formulation and to address each challenge as they arise. Eventually this process will arrive at a drug product composition that satisfies all necessary quality attributes. 

Example:
Adjusting a formulation by raising the pH to align with the target profile may impact the solubility of the API and cause the API to precipitate out, lowering the API concentration in solution. This will require even further development to achieve all criteria for the drug product. 

Getting Started 

Formulation development starts with developing the composition to meet the target profile, then designing the process to ensure it is manufacturable, scalable, and efficient. To begin the work, the following will need to be determined: 

  1. The target product profile
  2. The clinical phase the product will be used in
  3. A preferred container closure system
  4. The target cGMP batch size

After these items are determined, the CMO will optimize the formulation composition to meet all critical properties. Nearly all drug products will include targets for: 

Each of these are discussed below. 

Sterility

Sterility is critical for patient safety. A contaminated drug product can harm a patient. This aspect is addressed through a sterility assurance strategy. The most common being sterile filtration, aseptic formulation, and, when possible, terminal sterilization.

API Concentration

The correct API concentration is necessary for the drug to be effective. This target is determined by the sponsor, and often the biggest challenge to overcome is solubility. All solvents, including water, have a limit to how much solute it can dissolve. If solubility is low, then the target concentration may not be reached as the API may precipitate out of the solution before achieving the target concentration. There are several methods to increase the solubility of the solution to reach the API concentration, such as: 

  • Adding surfactants 
  • Adjusting the pH 
  • Using solubilizers or cosolvents 
  • Using complexing agents 

Once the target concentration has been reached, the focus shifts to addressing other critical physical and chemical properties, such as osmolality. 

Osmolality

The target osmolality is typically chosen to align with that of the injection site. If the osmolality of the drug product falls below the desired range, sodium chloride will be added to elevate it. Reducing osmolality is more difficult, and likely the best course of action will be to reduce the concentration of the API and increasing the dose volume. This decreases osmolality while maintaining the same API load per dose. For example, instead of administering a 1 mL injection with an API concentration of 3 mg/mL, the CMO may suggest a 1.5 mL injection with 2 mg/mL of API. The API load remains 3mg in both injections, but a lower osmolality can be expected in the second injection. 

pH

pH is typically chosen to align with the injection site and will often go towards a neutral pH. By matching the body’s natural pH, the injection may be less painful. Correcting the pH is straightforward. A base is added to adjust the pH up and an acid is added to adjust it down. 

Stability Matters

Once the drug product formulation has been determined, the next focus is to analyze and optimize the drug product for short- and long-term stability. 

Short Term Stability

The drug product should remain stable for the time and conditions it will experience during formulation, filtration, and filling activities. The product will need to demonstrate good stability at controlled room temperature for approximately one week to be considered “manufacturable”. Exceptionally temperature sensitive drug products may be prepared in and filled from a jacketed mixing vessel to keep the drug product cool to 5 – 15 degrees Celsius. 

Short term stability can be assessed by conducting a hold-time study. The drug product formulation is prepared under expected manufacturing conditions and sampled regularly throughout the study’s duration. The duration should extend for at least the maximum time required to formulate and fill the drug product. The samples are tested to determine if critical parameters fall out of range within the study’s duration and, if they do, at what point in time. If the parameters do not fall out of acceptable ranges, then the drug product is considered stable enough for production. If the product falls out of range near the end of the study, then changes to the process or limits to manufacturing may be implemented to correct the issue. If the parameters fall out of the acceptable range quickly (after a few days), then the formulation will likely require stabilizers or further formulation development to address short term stability. 

Long Term Stability 

The drug product should also have sufficient long-term stability. At least 12 months of stability is needed to maintain a continuous supply of medication to patients, but most target profiles will require at least 18 or 24 months of stability. 

Early stability analyses can help identify issues with long-term stability early in development without the considerable time investment involved with ICH stability studies. These are samples held at accelerated temperatures for three to four months. Samples are pulled and undergo quality testing to track degradation over time. Early stability analysis samples should remain within acceptable ranges even at the four-month mark under accelerated conditions to expect greater than 12 months of stability for the drug product. If these samples fall out of range during these accelerated studies, then further development is needed. Either the formulation composition, the process, or the container closure system will need to be adjusted. 

A Method to the Madness 

The development of effective parenteral medications is far from a trial-and-error endeavor. It is a methodical process, guided by scientific principles and strategic planning. The process of formulation development is to optimize the product so it adheres to the TPP, maximizes patient comfort, and remains manufacturable, scalable, and robust. Each step in the formulation process is deliberate and aimed at achieving a safe and effective drug product. 

More Information

For more information about formulation development, check out our webinar, The ABC’s of Formulation Development for Parenteral Drug Product Manufacturing. In addition to the topics discussed in this blog, the webinar covers: 

  • How to scale up a drug product formulation 
  • How to determine equipment requirements & material compatibility 
  • Which sterilization process to select for a drug product 
  • How to maintain homogeneity in suspensions 
  • How to address product sensitivities & viscous drug products 

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