Pharmaceutical Formulation Development
Formulation development is at the heart of drug development
Formulation development is the science of developing a dosage form that can be safely and effectively administered to a patient. Formulation scientists develop the dosage form by combining the active pharmaceutical ingredient (API) with inactive ingredients, also known as excipients. The inactive ingredients ensure that the dosage form is stable over its shelf life, releases drug at the desired rate and the right time and can be manufactured reliably and repeatedly. To achieve this, the formulation scientist can develop the drug as an oral solid dosage form (OSD), oral liquid formulation, topical formulation, ophthalmic formulation, or an injectable formulation, which are suitable for either cGMP clinical trial manufacturing or commercial manufacturing.
Why is it important to choose the right formulation development team?
To avoid costly delays and failure.
Formulation development encompasses many disciplines within pharmaceutical sciences:
- Chemical and material properties of the drug molecule and drug delivery systems must be considered to ensure regulatory compliance, stability, and proper drug release kinetics. Suitable inactive ingredients (excipients) and manufacturing process are then carefully considered and developed to ensure successful formulation development.
- Clinical pharmacokinetic requirements and drug delivery system mechanisms are crucial to achieve the required clinical goal. Drug molecules often have poor solubility, poor permeability, undergo first pass metabolism, or are unstable in gastrointestinal environments leading to poor bioavailability. The formulation scientist must be knowledgeable in bioavailability enhancement techniques to ensure that the drug successfully reaches the site of action to provide clinical benefit to the patient.
- When developing drugs for regulated markets, understanding regulatory requirements is important to avoid costly delays in both clinical and commercial drug development programs. At Vici, we are well-versed in FDA requirements and are able to work with the Agency to ensure that your clinical program is not hampered by FDA compliance related delays.
Vici has the experience and expertise needed to develop a variety of dosage forms:
- Oral solid dose (OSD) is the most common method of administering medicine. Oral tablets and capsules may be either immediate release or controlled release. Vici is experienced in developing a variety of formulations such as single layer or multi-layer tablets, coated tablets, enteric tablets or capsules, powder filled capsules, multi-particulate coated bead capsule formulations for controlled release, and mini tablets.
- Oral liquid formulations may either be solutions or suspensions depending on the drug load and its solubility. Oral liquids have the advantage of allowing for variable dosing and are more suitable for patients experience dysphagia.
- Buccal dosage forms are taken orally but are intended to release the drug substance in the mouth, where it is also absorbed. Buccal formulations may be suitable for API that have poor oral bioavailability due to lack of stability in the GI tract or first pass liver metabolism.
- Topical dosage forms may be creams, ointments, gels, or solutions. The type of formulation is selected based on the physicochemical properties of the drug substance and the indication.
- Injectable formulations may be solutions, suspensions, or solutions for reconstitution. Dosage forms for injection must be sterile.
- Ophthalmic dosage forms may be solutions, suspensions, gels, or ointments. They must also be sterile.
Formulation development for early phase clinical studies
Formulation development for early phase clinical trials (such as Phase I, Phase IIa, and Phase II clinical trials) and first-in-human clinical trials are performed in small scale to increase speed and decrease cost. The focus is to develop an effective formulation that is stable at least through the length of the clinical trial. A range of strengths are developed to support dose escalation studies. Being an R&D-focused CDMO, we are able to manufacture small prototype formulation batches that save money and can be manufactured quickly. Typically, we can develop first-in human clinical trial formulations and manufacture cGMP clinical batches in a matter of months.
Ingredient selection and regulatory compliance
Selecting the right ingredients is at the heart of formulation development. Depending on the dosage form and the target market, the right drug substance grade and source must be selected. We are experts in analytical method development and testing and also NDA and ANDA regulatory filing. We bring this expertise to bear when selecting active and inactive ingredients that ensure that formulations, we develop will comply with all required FDA requirements. Our sourcing team is experienced in sourcing such ingredients globally, so you don’t have to do this.
Formulation optimization
We perform rapid formulation optimization studies aimed at developing an effective, stable, and safe formulation that can be easily manufactured. Optimization studies are often performed utilizing design of experiments (DOE) concepts. Formulation optimization studies include:
- Optimization of drug substance (API) particle size
- Selection of inactive ingredients
- Selection of inactive ingredient grades and sources
- Optimization of inactive ingredient levels
- Drug-excipient compatibility studies
- R&D stability studies under accelerated conditions
- Small scale manufacturing process selection
- Developing drug product (or dosage form) specifications
- Optimizing pH for liquid formulations
- Taste masking studies (if required)
- Optimizing drug release rate for controlled release products
- Improving solubility and dispersibility for low-solubility drugs
- Improving bioavailability
Manufacturing process development and scale-up
The manufacturing process goes hand in hand with the formulation in producing a high-quality pharmaceutical product. As development transitions from early-stage to later stages, the manufacturing process must be scaled-up to produce a larger number of dosage forms suitable for phase 3 clinical studies, exhibit batches (terminology used for ANDA registration batch manufacturing) manufacturing, manufacturing process validation batches, and commercial batches. As the manufacturing process is scaled up, scientists and engineers must ensure that the critical-to-quality attributes (CQA) of the formulation do not change. Our formulation development scientists and manufacturing process engineers work hand in hand in designing, optimizing, and scaling up the manufacturing process and can make sure that drug products meet specifications at all stages of its life cycle.
(note – need a new page on manufacturing process development, optimization, and scale-up)
Formulation development for Phase III clinical studies
Pivotal clinical batches, also termed registration batches or exhibit batches for ANDA filing, may be manufactured. The manufacturing process is scaled up to at least be able to produce 100,000 units for oral dosage forms or at least 1/10th the commercial manufacturing scale for liquid and semi-solid topical dosage forms. The analytical test methods must also be fully validated (internal link to validation page) at this stage and the final drug product specifications must be set. The product must also meet the criteria for NDA or ANDA filing in terms of stability through accelerated, intermediate, and RT stability studies (internal link) to establish shelf life.
At this stage, the formulation must be fully optimized, and the manufacturing process thoroughly studied for robustness and repeatability. The manufacturing process parameters must be optimized such that they are not at an edge of failure. Quality-by-design and six sigma principles are often applied just prior to this stage to ensure the highest possibility quality. Failure to do so at this stage could result in a significant increase in cost and time for completion. At Vici, we are experts at both formulation development and manufacturing process development and troubleshooting. (introduce a call to action here and link)
Formulation development for generic drug development (for ANDA filing)
Generic drug development for ANDA filing follows a more defined path and typically must be done quickly and efficiently. Generic drugs must be bioequivalent to the marketed reference product (RLD or RS) as demonstrated through in vitro equivalence testing or in vivo human pharmacokinetic studies to establish bioequivalence (link to blog). To promote the introduction of cheaper, high-quality alternatives to expensive branded drugs, the FDA has introduced a set of guidelines to help manufacturers seek and gain ANDA approval. Vici is very experienced with the entire process and can handle projects end-to-end to develop and receive ANDA approval on your behalf. Briefly, the development pathway is as follows:
- Select the reference drug for which a generic alternative must be developed
- Procure the RLD or RS and characterize the product including undertaking Q1/Q2 de-formulation if required
- Select API source, ideally with an approved US DMF (https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs) and evaluate multiple options if available
- Develop analytical test methods
- Determine formulation development strategy and initiated early-stage R&D studies
- Develop suitable generic prototype formulations with matching characteristics including dissolution, assay, impurities, and R&D initiate stability studies
- Perform pilot bioequivalence clinical study, if necessary, make changes to the formulation based on results if required
- Perform the manufacturing process optimization and scale-up studies
- Validate all analytical methods
- Manufacture the exhibit batch (three batches per strength utilizing at least two different lots of API)
- Perform pivotal clinical bioequivalence study per FDA’s published product-specific guidance (https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development), if necessary,
- Place the finished product in its final packaging configuration on accelerated, intermediate, and real-time stability
- Prepare the ANDA meeting all requirements, especially FDA’s refuse-to-receive (RTR) guidance (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/anda-submissions-refuse-receive-standards-rev2)
- File the ANDA upon receiving successful 6-months stability data
Why is it important to choose the right formulation development team?
Formulation development encompasses many disciplines within pharmaceutical sciences:
- Chemical and material properties of the drug molecule and drug delivery systems must be considered to ensure regulatory compliance, stability, and proper drug release kinetics. Suitable inactive ingredients (excipients) and manufacturing process are then carefully considered and developed to ensure successful formulation development.
- Clinical pharmacokinetic requirements and drug delivery system mechanisms are crucial to achieve the required clinical goal. Drug molecules often have poor solubility, poor permeability, undergo first pass metabolism, or are unstable in gastrointestinal environments leading to poor bioavailability. The formulation scientist must be knowledgeable in bioavailability enhancement techniques to ensure that the drug successfully reaches the site of action to provide clinical benefit to the patient.
- When developing drugs for regulated markets, understanding regulatory requirements is important to avoid costly delays in both clinical and commercial drug development programs. At Vici, we are well-versed in FDA requirements and are able to work with the Agency to ensure that your clinical program is not hampered by FDA compliance-related delays.
Dosage Form Development & Manufacturing
Our expertise across dosage forms includes capabilities for:
