For small molecule parenteral formulation development, the interplay between solubility, local tolerance and systemic toxicity is key for a successful formulation development needing a minimum of resources and time. Our DPS experts have a significant experience in developing parenteral small molecule products and a track-record of bringing products to the clinic and the market.

Small molecules are often characterized by very low aqueous solubility, and this is the first challenge for delivering small molecules parentally. However when focusing only on solubility and stability during formulation development, there is a risk of detecting local tolerance limitations, systemic toxicity or hypersensitivity issues during preclinical testing, making a later reformulation necessary. Our parenteral formulation experts have an extensive track record in balancing these challenges so that reformulation is avoided.

The feasibility of different solubilisation techniques is systematically verified based on a formulation decision tree, which considers e.g. charge modification by pH adjustment, micellarisation, co-solvency, cyclodextrin-chelation, emulsification. Freeze drying is also proposed when appropriate. Complex drug dosage forms such as emulsions or liposomes are taken into consideration when no more straightforward techniques are possible, since these approaches entail significantly more resources and costs.

Our DPS experts have a significant experience in developing parenteral small molecule products and a track-record of bringing products to the clinic and the market.

The panel of drug product services for small molecule parenteral development includes:

  • Optimized pre-formulation studies focussing on parenteral dosage forms
  • Stress-testing (sensitivity towards oxygen, metal-ions, light, heat)
  • In-silico evaluation of pre-formulation data and proposal of formulation types with high likelihood of success
  • Comprehensive high throughput solubility studies 
  • In vitro haemolysis of heparinised human blood and miscibility with plasma as surrogate markers of local tolerance 
  • ICH stability studies 
  • In-use compatibility studies
  • Development of Target Product Profile (TPP)
    The target product profile (TPP) serves to provide a format for discussions between a pharmaceutical company and health authorities, that can be used throughout preclinical and clinical development towards commercialization as well as postmarketing activities. The TPP aims to define the future desired product elements and aspects, that development should strive for, including overall intent as well as details, such as elements relevant for parenteral product development. These include indications and usage, dosage and administration (route, e.g., intravenous, subcutaneous, intravitreal, intrathecal, interarterial, and administration volumes), dosage forms (e.g., liquid, lyphilisate) and strengths, primary packaging and device (e.g., vial, syringe, autoinjector, pen in cartridge), storage and handling. 

    Our DPS team helps our customers to define the TPP and tailor the ideal development strategy from a drug product perspective, to ensure a robust commercial product in the end, with a most suitable development strategy related to speed but also quality and chance-of-success.
  • The physicochemical properties of small molecules regulate their solubility behaviour. In-silico determination of the molecule’s physicochemical parameters (such as pKa, percentage of ionized species at specific pH and log P) can guide subsequent solubilisation studies and reduce the time and resources required for this important activity.
  • High-throughput evaluation of solubility is performed using the state-of-art robotic system at our DPS, which allows a rapid and comprehensive estimation of solubility and solubilisation options with small material requirements.
  • Early-stage pharmaceutical development aims to very quickly develop a formulation that is appropriate for use in preclinical (GLP) studies, early-stage clinical studies (e.g., phase 1, 2a) and considering the future commercial image and target product profile. Time to entry-into GLP tox and time to IND/CTA filing and first Clinical Study start is key, however safety of healthy volunteers, and insurance of product quality to ensure representatives of material is most important. Based on preformulation and/or information provided by our customers, we tailor the early-stage formulation strategy according to the molecule format, type and specific sequence, in order to guarantee significant speed, whilst ensuring quality and never compromising patient safety, and by having late-stage development and commercialization in mind. Our formulation strategies consider not only stability, but also TPP-relevant primary packaging as well as drug product manufacturing process designs and patient use.

    Early-stage formulation options are based on our unmatched experience and prior knowledge, and each program outline is discussed and agreed with our customers prior execution. As dosage forms, liquid dosage forms are usually preferred, but freeze-drying (lyophilisation) is also employed where required.
  • Late-stage pharmaceutical development aims to ensure that the drug product design intended for pivotal clinical studies (e.g., phase 3) and filing of BLA/MAA and commercialization is adequately robust, with regard to stability, but also all other elements of the TPP, including administration and use. The appropriate design of dose strength per unit dose container, appropriate selection and qualification of primary packaging, potentially, the integration with a parenteral device such as autoinjector or pump are just a few considerations for a robust formulation.

    As dosage forms, liquid dosage forms are usually preferred, but freeze-drying (lyophilisation) is also employed where required.

    Our DPS team has a history of having developed a number of formulations for commercialization.

  • Since the drug product must be sufficiently robust for commercialization, it is important to evaluate and study all its parameters and assess them for criticality. This includes choices of excipient suppliers and related excipient quality, choices of primary packaging and related quality, as well as evaluating the impact of qualitative and quantitative changes in the composition (potentially critical formulation parameters), within normal operating ranges during manufacture as well as beyond on the products critical quality attributes. Such formulation robustness studies support product understanding, evaluating design space and threshold of potential failure, failure modes and finally, setting relevant specifications for the product lifecycle and health authority submissions.
  • Formulations and drug products may undergo further improvements as life-cycle management and line extension activities. For example, it may be found after actual development, that subcutaneous use may be more advantageous over intravenous use, requiring a new formulation to be developed and launch, or finding that a syringe and autoinjector may be preferable and should be launched in addition to a standard vial configuration. These line extensions can help to improve patient convenience and use, may provide competitive advantages and provide options for intellectual property.

    Our DPS team has experience in evaluating and suggesting options for parenteral product line extensions and life-cycle management and support in developing and launching these.

  • Parenteral products need to be administered correctly, to ensure patient safety and product efficacy. This is to make sure that patients are receiving the right dose of the active ingredient with appropriate quality. Hence, Health Authorities globally place a high emphasis on providing data to support the in-use stability and compatibility during administration of parenteral drug products. Many biological moieties can show different incompatibilities with administration device, including adsorption, precipitation, particle formation or glycation. Specific challenges can occur with products that have to be dosed in very low amounts and/or with very broad dose range, such as products under so-called  “MABEL” dosing per European guidances.

    With the large variety of options for administration devices and materials that are available for drug administration globally, this can become a daunting activity. 

    Our DPS team has a wide experience in this field, and can support in designing and executing the in-use and compatibility study and selecting the best options that ensure patient safety as well as clinical and commercial success of the program.

  • Small molecule formulations may imply the use of non-aqueous components that may or may not be critical. Our DPS experts have designed a unique, proprietary and specific assay that assesses potential incompatibility with human blood.
  • Preferably, parenteral products need to be terminally sterilized to ensure best sterility assurance levels. Sterilization methods include heat sterilization, autoclaving, gas or chemical sterilization. Lonza’s experts can evaluate various sterilization methods with regards to product quality impact, and drive suggestions for an adequate process selection. If terminal sterilization is not warranted, we can support aseptic manufacturing, with the use of sterile filters, such as usually employed for biologics, or explore other options with our customers.

Meet the expert

Dr. Dieter Röthlisberger, Head Drug Product Technical Project Leaders

Dieter Röthlisberger has more than 30 years of experience in Pharmaceutical and Analytical R&D. During his career, he has held various positions in formulation research and development, drug product development (sterile and oral liquid and semi-solid dosage forms), GMP manufacturing (biopharmaceuticals and small molecules), as well as outsourcing coordination (parenteral dosage forms). Dieter has also supported absolute bioavailability, mass balance, microdosing, radiolabeled or positron emission tomography (PET) studies. His pharmaceutical experience includes: liquid solutions, lyophilisates, micelles, liposomes, suspensions, emulsions for parenteral administration, syrups, suspensions, eye drops as well as semi-liquid and liquid filled capsules as oral dosage forms.

Dieter holds a Ph.D. in Medicinal Chemistry and graduated in Pharmacy from the University of Lausanne (CH). He is lecturer at the ETH Zurich (Master Degree Pharmaceutical Sciences: Module Drug Product Development and Industrialization).