Want a smooth regulatory process? Here’s how to document.


As a CMO involved in the manufacture of drug substances or Active Pharmaceutical Ingredients (API), PCI Synthesis uses this asset in a robust strategy for supporting complete and successful drug applications. As each unit completes its function in pursuit of the common goal of a successful New Drug Application (NDA) or Abbreviated New Drug Application (ANDA), the organization is equipped to collect information from each unit and compile it into a cogent presentation for regulatory and scientific review. PCI Synthesis has acquired a comprehensive understanding of the documents, reports, and other information that should be collected along the development and manufacturing paths. This documentation may be characterized as addressing Technical, Scientific and Administrative requirements.


The primary technical document in support of an NDA or ANDA is the Drug Master File (DMF). This master document compiles the Chemistry, Manufacturing and Controls (CMC) information for the drug substance, in compliance with instructions contained in guidance documents from the US Food and Drug Administration (FDA) or the International Conference on Harmonization (ICH). The DMF is formatted as a Common Technical Document (CTD), and organized to fulfill the Drug Substance sections of Modules 2 and 3 in the CTD. The full DMF is submitted in paper or electronic format to the FDA’s Center for Drug Evaluation and Research (or other international regulatory agencies, as required), with authorization to access its contents in support of an application. PCI Synthesis, as the DMF Holder, will make available the “open” portion of the DMF to its contract partners. The open portion of the DMF includes much of the critical information that must be shared between PCI Synthesis and the applicant.

The technical information of first importance is a summary of the manufacturing procedure. While the proprietary details of the manufacturing process are only included in the full DMF, an abbreviated narrative or process flow diagram provides identification of raw materials, solvents, and intermediates and their order of appearance in the process. These compounds may be potential impurities in the drug substance.

A second group of critical technical documentation is the analytical methodology used to test the drug substance. PCI Synthesis uses these methods for release of the drug substance, and the applicant uses them for release of the drug substance as a raw material for its formulation. Validation reports for the methods for assay, impurities and residual solvents are included in the open portion of the DMF, along with reports on forced degradation studies performed on the drug substance. These reports demonstrate that the methodology possesses stability indicating properties. Also, full qualification reports for reference standard material used in the test procedures are included.

Finally, documented analytical results for batches made by the manufacturing process and tested by the approved methods must demonstrate compliance with specifications established by PCI Synthesis and the applicant. This data includes full release testing at the completion of the manufacturing process, as well as appropriate stability testing for both short-term accelerated and long-term ambient studies. A statement that the drug substance does not contain Organic Volatile Impurities, confirmed by testing, also appears. This data, as well as approved Certificates of Analysis, is included in the open portion of the DMF.


The open portion of a DMF also includes reports on various scientific studies essential to the applicant’s preparations. The first essential scientific document is a chemical description of the API impurity profile, which includes raw materials and intermediates that have the potential to carry through into the final product, as well as all possible degradants and products of side-reactions that may occur during the process. The second essential document in this category is a well-articulated and scientifically sound rationale for the manufacturing process, with special attention to the selection of the API Starting Material. A third important report is a justification for the drug substance specifications, especially those for assay, impurities and residual solvents.

Beyond the open portion of the DMF, PCI Synthesis provides additional scientific information in support of a successful application. For example, an API manufacturing process that uses key raw materials or an API starting material derived from a plant source may prompt questions during regulatory review about the harvesting of that source. PCI Synthesis works with its own suppliers to help the applicant compile a comprehensive Environmental Impact Analysis for its application.


As a manufacturer of regulated drug substances, PCI Synthesis is attentive to the administrative documentation required to maintain proper relationships with its contract partners and regulatory agencies. The proper composition and maintenance of this documentation is critical to ensuring a successful regulatory submission. For each of its manufacturing sites, PCI Synthesis regularly submits updated registration information with the FDA. Drug Master Files also receive periodic administrative updates, including Letters of Authorization for partners that list PCI as a supplier of API in their drug product applications. Copies of these documents are provided to applicants as requested. In addition, commercialized drug substances used in approved drug product applications require filing appropriate drug listing documentation with FDA or other regulatory agencies, with changes or amendments updated as needed. Lastly, PCI Synthesis continually updates its internal administrative documentation, including protocols and standard operating procedures, to maintain full compliance with current Good Manufacturing Practices that are reviewed by FDA during product Pre-Approval Inspections or GMP System Compliance audits.