Outsourcing: Pre-formulation and Formulation for Preclinical and Clinical Studies
Sudhakar D Garad, Ph.D.Group HeadChemical and Pharmaceutical Profiling GroupNovartis Institute for Biomedical Research
Introduction
For any new chemical entity (NCE) to enter into the market, it takes about 7-12 years and this cost up to 0.8 - 1 billion dollars (1, 2). There are a number of steps involved to enter a new chemical entity from research to market. The first and most important hurdle for any molecule is to have favorable pharmacokinetic (PK) parameters with desired pharmacodynamic (PD) effect with minimum or no toxicity issue (wide therapeutic window) in animal models before it enters into development. While evaluating PK, PD and therapeutic index in preclinical models, it is important to carry out all these studies with a crystalline, soluble, stable (physical / chemical), bioavailable NCE's at different doses. During the preclinical stage less importance is given to the physical form of NCE's. Many times, preclinical studies are carried out using a solution (co-solvent based) or suspension (amorphous free form or a salt form) of NCE's. Both the dosage forms have their advantages and disadvantages as shown below in Table 1.
Data generated using suspensions is more relevant to clinical formulation, if NCE needs to be developed as a pill or capsule. However, in screening phase it is too early to think about clinical formulation when more than 100 compounds are screened for a single target. In the screening phase, it is advisable to understand PK with solution which is physically and chemically stable across pH. When the PK profile of a compound looks promising (more than an hour half life, low clearance) it is very important to understand PK from stable, crystalline developable form before it enters into efficacy and tox study. This data helps development scientists to design and formulate phase I clinical formulation within a short period of time.
Clinical formulations are usually drug in capsule or powder in a bottle or a solution. Tablets are preferred as well, but it is very rare to develop tablets for phase I because quantity required to make tablets and optimize formulation is high and, secondly the molecule has to be biopharmaceutical classification system- BCS I or III (high solubility/ high permeability, high solubility/low permeability respectively) (3). Because in Phase I clinical trial, multiple doses are administered and exposure should not be limited by solubility or dissolution rate. Each dosage form has its own importance. Powder in bottle is recommended when the exposure is not limited by solubility/dissolution rate, such as BCS I and III molecules. Powder in a bottle is also recommended for BCS II molecule for low dose study design with minimum volunteers/patients in exploratory investigational new drug application (e IND) (4). Drug in a capsule is recommended for BCS class I, II and III molecules provided a good in vitro-in vivo correlation has already been established and confirmed in preclinical models that exposure is not limited by solubility/dissolution rate. Drink solutions are usually recommended for BCS II and IV, where exposure is limited by solubility and permeability respectively. Once the final
dose is calculated it is worth to perform a BA/BE study with solution vs. solid dosage form and pursue the right dosage form strategy depending on the outcome of the study. Solid dosage forms (tablet/capsules) are most widely preferred because of patient compliance and longer
shelf life of the dosage form. Advantages and disadvantages of solution vs. suspention in pre-clinical studies are given in table 1.
Therefore, it is very important to understand overall strategy for the given project and accordingly needs to plan outsourcing activities. There are advantages and disadvantages of outsourcing as described in Table 2 (5).
In this article the author would like to cover the following topics:
1. Selection of contract research organization (CRO)
2. Pre-formulation studies
3. Preclinical formulations
4. Pre-clinical in vitro data
5. Clinical formulations
6. CMC documentations for investigational new drug (IND) filing
Selection of CRO
Quality Assurance (QA) Audit
In a small or big pharma, the QA staff is aware of all the processes involved from preclinical to market for any new chemical entity. The
staff must be experienced in chemistry, manufacturing and control technologies. When QA staff visits CRO for an audit, they are involved in laboratory inspection, review of standard operating procedures (SOP's). When CRO complies with all the above requirements, usually sponsor proceeds in initiating activities.
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