Facilitating Rapid Introduction of New Chemical Entities: Part 2
By David Johnston, President, Oread Laboratories
This two-part article by Oread CEO David Johnston discusses, from a contract manufacturer's perspective, how pharmaceutical companies can speed up introduction of new chemical entities. To read Part 1, click here.
• Preformulation, Formulation Development, and Pre-Clinical/Clinical Trial Supplies
• Stability Studies (ICH)
• Drug Safety
• Technology Transfer Considerations
• Regulatory Acceptability of the Work Being Outsourced
• References
Preformulation, Formulation Development, and Pre-Clinical/Clinical Trial Supplies (Back to Top)
In preformulation testing, the capability to conduct physicochemical and physicomechanical characterization of API, dissolution studies, and short-term accelerated stability studies is essential. A full range of properties in solution—e.g. solubility studies (intrinsic, pH, etc.), determination of dissociation constants, hygroscopicity, and lipophilicity—are needed. Similarly, solid state properties, such as bulk density, flow, and compression properties, and methods to evaluate the impact of various salt forms on physicochemical properties of drug substance are necessary to demonstrate rational formulation development.
These preformulation studies will also identify suitable excipients and which might be used in the manufacture of dosage forms. Where the excipients selected are novel, or are being used for a novel purpose, a close collaboration with the drug safety group provides rapid decision making as to what additional safety studies might be required. The dosage form of choice will be based on the strategy adopted and the results derived from the preformulation studies.
Such early dosage forms will be subjected to a variety of stress or accelerated stability evaluation conditions to provide some early indication as to their suitability for longer-term development and to assure the safety of patients. Again, in order to support these efforts a discriminating, stability indicative assay method will be developed to evaluate these early stage products. The evaluation of any new impurities developed in these products is particularly important at this early stage since they will need to be considered in terms of the safety studies to be performed.
Formulation development uses the information derived from the pharmaceutical chemistry and preformulation studies to develop dosage forms that allow the active ingredient(s) to be delivered to the site of action in the body. Again, information derived from the drug safety studies, in particular metabolism and pharmacokinetics as well as from pre-formulation, is used to determine the best dosage form. There are, of course, many options for early stage product formulations, and these can range from simple solutions for oral, IV, or topical administration to suspensions, capsules, or tablets for oral administration.
At the early stage in development, the simplest dosage forms, i.e. the solution or the suspension, will likely be used for the safety studies. Whether these can also be used for the human studies will depend on both the clinical and regulatory strategy chosen and, of course, other critical factors such as the stability of the dosage form for the period of the clinical study. The evaluation of the drug candidate in animals and humans will include a careful evaluation of how the active entity is transformed in the body. The primary goal is to understand the metabolic profile of the candidate, i.e. how much transformation occurs and what the end products of these transformations are. In addition to the ability to detect and identify the metabolites, close interaction with the synthetic chemistry group can provide an opportunity to independently synthesize these molecules for use in further studies.
Based on the information from the early stress studies of the API and preliminary drug dosage forms, the clinical dosage form will be selected. Following careful evaluation of the animal safety and efficacy data, the range of doses for the clinical studies will be defined. A key component of these early safety studies will be a pharmacokinetic assessment of whether the drug candidate is being absorbed and how long it remains in the bloodstream. Interim testing monographs will be developed for the selected dosage forms and will include the assay and impurity test methods already noted. These will also include the addition of other chemical, physical, and microbiological tests consistent with the nature of the product.
These drug products for use in clinical trials will be manufactured, packaged, and controlled under cGMP and placed on formal stability evaluation under protocols consistent with the ICH guidelines. Typically, these drugs are manufactured in batches that are much smaller than those made in a pharmaceutical company's normal large-scale manufacturing facility. Packaging and labeling of drugs for clinical trials is a vital function to the successful conduct of a clinical trial. This highly specialized service not only packages the drugs in individual "blister" packages, but is custom designed to reflect the nature of the trial, number of patients, location of sites, different dosages for different patients, some with or without placebos, etc.
Clinical trials and packaging is a crucial and fault-intolerant part of the clinical trial process. Labeling for double blinded tests and concurrent data entry and product classification must be performed perfectly, on time, and consistently, and the information transferred to the client. Of course, the execution of these activities requires very close collaboration between the preclinical, clinical, and regulatory functions.
While clinical trials are going on, manufacturing methods for commercial development are set into place. Final methods, including place of manufacture and source of raw materials and of bulk drug (the active ingredient or ingredients in a drug) are also determined. One consideration when outsourcing the broader aspects of formulation development and drug product manufacture is the same issue noted earlier for API manufacture: What is the capability and capacity of the formulation group to develop and scale up the drug dosage form? The needs for phase I, II, and III and moving on through commercialization will be very different with only a few dosage units being needed for phase I, while millions of dosage units may comprise the batch size at commercialization. All of this information becomes part of the New Drug Application (NDA) that is sent to the FDA at the end of the trials
Stability Studies (ICH) (Back to Top)
Stability studies are conducted as an ongoing process throughout the development program to insure the stability of the API and dosage form throughout the time period of the preclinical or clinical study being conducted. The variables tested include exposing the API and/or product with differing levels of protection (packaging) to heat, light, and humidity at varying degrees for various periods of time from months to years. Stability is an ongoing process that begins in the pre-clinical stage, but is ongoing through the clinical as well as post-approval manufacturing stages. In pre-clinical studies, stability testing is necessary to determine the short-term effects on both the drug substance as well as the final dosage form from light, heat, and humidity at varying degrees and ranges. Degradation of the compound at the pre-clinical stage could result in reformulation, specific storage instructions, or the canceling of the development due to the instability.
Satisfactory stability studies lead to the development of a commercial shelf life of several years for the product—a key feature for successful marketing. Much of the approach to this part of the development process has been rationalized and accelerated with the guidelines developed through the ICH discussions though differences in interpretation of factors such as matrixing may continue to be problematic (Reference 2) in terms of how much time may be saved.
Drug Safety (Back to Top)
As noted in the preceding sections, the close integration of many of the safety studies with the other preclinical activities facilitates decision making and thus the development process. The strategy behind the drug safety evaluation is obviously based on the regulatory requirements that have been defined through the ICH process. Close collaboration between the clinical and drug safety groups since the safety studies are designed to allow the dosing regimen and strategy defined in the clinical trial protocols. Pre-clinical safety studies involve the testing of both raw active ingredients as well as APIs that have been formulated in the CMC process on laboratory animals to measure various interactions of a drug compound and its various forms. These interactions are measured to deduce the method of reaction, as well as to determine the optimal dosage and levels of safety evaluation.
When combined with the determination of blood levels of the drug under development, a clear understanding of the toxicokinetics of the molecule can be derived. The increasing use of high-speed sensitive tools such as HPLC/mass spectroscopy have completely transformed both how much information can be obtained and the quality of day for consideration. This can give a broader evaluation of the safety margin of the drug, including specific organ toxicity and more specific studies, e.g. teratogenicity studies where the potential impact on the fetus might be evaluated. As with other preclinical development activities, the drug safety evaluation goes in parallel with the entire development process, and the studies become larger and longer in duration.
Similar to other areas of development, the rational development of safety studies relies on the detailed understanding of related properties. For example, to be certain that safety studies insure adequate exposure of the test material, a complete range of absorption, distribution, metabolism, and excretion (ADME) studies needs to be completed. These can include the determination of blood/plasma concentrations, tissue concentrations, mass balance studies, biliary excretion studies, placental transfer, lacteal transfer, absorption site studies, enterohepatic recirculation, protein binding, and metabolite identification. A number of these studies may be facilitated by the use of isotopically labeled molecules as probes.
Whole-body autoradiography (WBA) can provide information on drug distribution in tissues and organs that is not obtainable by other methods. Individual tissues, such as brain and eye, can be independently sectioned to analyze localization of the radiolabeled entities in various areas of the strata. Highly refined macroautoradiographic techniques allow timely completion of both qualitative and quantitative autoradiographic studies. Phosphor imaging (autoradioluminography) technology, coupled with advanced image analysis software, vastly reduces turnaround time while offering very precise results. This capability is offered by only a few contract organizations.
Technology Transfer Considerations (Back to Top)
Throughout the drug development process, many activities will be running in parallel, and these may either be done in house—within the innovator's laboratory—or at one or more contract laboratories. I have previously described (Reference 1) some of the considerations that should be taken into account when trying to identify a CRO. When considered across the broad spectrum of preclinical disciplines, the number of technology transfers both into and out of the contract development organization could be considerable and a potential area where delays could occur. In order to ensure that these are all effectively executed, it becomes critical that the interfaces, both within and between development activities at different locations, are very effectively managed. This requires a high level of skill in the technology transfer process and a high level of skill in managing increasingly complex programs.
Regulatory Acceptability of the Work Being Outsourced (Back to Top)
Underlying all of the above will be the development of the regulatory preclinical information that will be collected in parallel with study execution. The practice of capturing reported information as it is generated would allow the completion of the preclinical component of any submission, be it CTX, IND through marketing application, within a few weeks of the studies being completed. In support of this, all of the outsourced studies must be conducted in compliance with current good practices, GLP, GMP, and GCP as applied throughout the pharmaceutical industry. Similarly, the qualification validation and calibration of all systems used in producing or manipulating regulatory data must be capable of withstanding detailed regulatory audit.
In conclusion, the continuing drive to reduce the timeframe of the drug development cycle will result in increasing integration of the preclinical development functions. These functions will provide a continuous range of services throughout the discovery-development continuum to insure that the efficiency and effectiveness of the development process is enhanced. This shift in paradigm will be inclusive of the mainstream pharmaceutical industry and the contract pharmaceutical organizations, which will continue to evolve the skills to meet the challenges of this new paradigm. The increase in speed will be accompanied by no loss in quality but an improvement in processes that insures the conduct of rational development programs and the rapid transfer of information with increased assurance of quality data. As processes continue to evolve, it is important we remember a well-used saying that "measurement is the key to understanding" and measure the effectiveness of the new processes. With the knowledge, which comes from measuring what has been achieved, will come the opportunities for further advancement in how to do business.
- D Johnston "Technology Transfer as a Consideration when Outsourcing Pharmaceutical Product Development Activities", European Pharmaceutical Contractor November 1997,
- DJ Pack, "The ICH guideline for Stability Testing—What Matrixing Does it Permit?" Drug Information Journal, 1998, 561-567.
For more information: David Johnston, President, Oread, 1501 Wakarusa Dr., Lawrence, KS 66047-1803. Tel: 785-749-0034. Fax: 785-749-1882.