Utilizing Chemical Analysis throughout the Drug Development Process

Developing a new pharmaceutical product involves a complex progression of steps which require innovators, formulation experts, and manufacturers to coordinate their efforts in order develop an effective and safe product which complies with federal regulations. From initial product formulation to validation and stability studies, chemical analysis services are necessary during each stage of the development process in order to bring a new drug product to market.

The drug development process is broken into four phases, the pre-clinical phase and the clinical trial phases 1, 2, and 3. Analytical chemistry is used throughout all of these phases, yet its use in the process is more clearly segmented by the submission of the FDA’s Investigational New Drug (IND) and New Drug Application (NDA). The three primary chemical analysis categories are outlined in the table below, followed by a description of the major chemical testing services that are performed during the development of a pharmaceutical product.

The Drug Development Process According to Chemical Analysis Procedures

Pre-Clinical Services for IND Submission
The pre-clinical phase of drug development uses analytical chemistry to create and confirm both the safety and suitability of an initial formulation to be used in human trials. Once the Active Pharmaceutical Ingredient (API) is thought to have the desired effect on a particular disease state, the active compounds are synthesized for formulation. Solid form drugs undergo a series of preformulation exercises including salt selection, polymorph screening and excipient selection. Salt selection is primarily concerned with dissolution and the salt is chosen based on how its properties will affect the absorption of the drug. Polymorph screening is performed to ensure that the appropriate solid state crystal form is used in the formulation. Excipient compatibility is testing is performed during preformulation to confirm that the chosen excipients will not adversely interact with one another or the drug substance, and are suitable to use in the drug formulation. Salt and excipient selection are also routine for oral solutions, with the common addition of taste masking components chosen at this stage. These decisions determine much about the initial formulation, though the drug product at this stage is only intended for first-in-man clinical trials focused on safety testing, and so the final formulation is usually not established at this stage.

The IND Application details the testing requirements a new drug product must comply with in order to be approved for clinical trials. Methods are developed and may be validated at this stage to assay the drug product to ensure formula potency and consistency; as well as to create the standardized tests that will be necessary to ensure this consistency in the future. Typical tests include API assays, impurity monitoring, and dissolution properties, critical for assessing the drug product’s stability over time.

The formulation must undergo stability testing to prove that the drug product’s potency, as well as other properties, will maintain consistency throughout each clinical trial conducted. A forced degradation study may be performed as part of method validation to determine that the analytical method is sufficient to detect degradant products during stability testing. Further, the drug product must be tested in three mammalian species to ensure safety prior to first-in-man clinical studies. At the conclusion of these procedures the IND is submitted to the FDA for review, and if accepted the pharmaceutical product can move forward into clinical trials.

Chemistry Services during Clinical Trials for NDA Submission
The clinical trial phases of the drug development process provide information as to the safety and efficacy of the drug in humans. These studies are broken into phases 1, 2 and 3 and take tremendous time and money to perform. The results of these studies determine whether or not the product will be approved for introduction into the market. During the clinical trial period, the formulation of the drug product is finalized and decisions regarding packaging are made. All analytical methods for the drug products are then finalized and validated. Stability testing on the final formulation, in the final packaging, using the validated methods must be performed prior to the NDA submission and occurs during this time. Finalizing the formulation and packaging also means the final product specifications must be set to test the product on release and stability, all with validated methods. All release specifications must be met on both product release as well as stability testing.

Analytical method development and method validation services are performed in order to create and document the procedures necessary to:

• Assay the API
• Confirm the purity and identity of all raw materials
• Perform release testing
• Perform stability testing (6 months at 40C/75RH, and 2 years at 25C/60RH)

Extractables and leachables studies are also performed at the point at which final formulation and package selection are completed. This is to ensure that no substances are extracted from the product’s container or packaging into the pharmaceutical product that would cause a risk to health.

Manufacturers must demonstrate their full-scale process on three manufacturing validation batches all of which must pass all release test requirements in order to get approval for the final manufacturing process. Finally, the completed new drug application (NDA), with all chemistry, manufacturing and controls, as well as complete three-phase clinical studies are submitted to the FDA for approval.

Analytical Chemistry Support Post Marketing Approval
Though the drug development process is officially complete after the NDA is approved, chemical testing and analysis of the drug product continues. Manufacturing issues often arise after the product’s release into the market that must be mitigated through the use of analytical chemistry.

Some of the services utilized during this phase are:

• Counterfeit analysis to investigate claims of falsified medication
• Contamination identification to identify unknown impurities found in the product
• Failure analysis to discover the source of a manufacturing defect

At times, post-approval changes are sought by pharmaceutical manufacturers. Approval for these changes must be supported by the same rigorous testing that went into the NDA. Methods may need to be re-developed and re-validated and stability testing may also need to be repeated.

Additionally, some manufacturing issues require litigation support from analytical chemists to investigate product errors and to potentially serve as expert witnesses. The need for after-market investigative chemical analysis can occur at any time during the production process, even years after the drug product is released into the market.

Irrespective of the development phase, chemical analysis services have an ongoing role in the drug development process and are necessary to:

• Allow the development of the optimal formulation of the drug product
• Ensure product potency and stability
• Develop the standards to which the drug must meet in order to be released into the marketplace
• Ultimately, fulfill IND and NDA requirements for product approval

Avomeen Analytical Service is a distinguished provider of these services and provides support throughout the life cycle of a pharmaceutical product. Avomeen’s experts have decades of experience in performing chemical analyses on pharmaceutical products and can solve even the most complex pharmaceutical problems, which makes Avomeen the clear choice when choosing a laboratory to help create safe and effective drug products.

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