Guidance reviewICH guidances. The definition of a starting material, as presented in ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, reflects the diverse source of potential starting materials and notes that chemical properties and structure are normally defined (6). The focus is for field inspector use (CGMP) rather than marketing authorization application (MAA) or new drug application (NDA) review. It defines what may be considered a starting material, rather than how to select the starting materials for a synthesis from, for example, the raw materials and the intermediates.
A starting material can be defined as a raw material, intermediate, or a drug substance that is used in the production of a drug substance and that is incorporated as a significant structural fragment into the structure of the drug substance. A starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house and is normally of defined chemical properties and structure.
ICH Q8 Pharmaceutical Development introduces the concept of design space and a more science-based approach to the regulatory control of the manufacture of pharmaceutical products with potential benefits of reduced regulatory oversight for postapproval changes (2). The concepts of ICH Q8 apply to drug substances and drug products.
ICH Q9 Quality Risk Management provides guidance on a systematic approach to quality risk management for pharmaceutical products (3). The evaluation of the risk to quality should ultimately link back to the protection of the patient, and the quality risk-management process should be commensurate with the level of risk and based on scientific knowledge.
FDA's Guidance for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances noted that what constitutes a starting material may not always be obvious. The following criteria may be helpful (7):
The final intermediate can influence the selection of the starting materials and is defined by FDA as follows (7, 8):
The last compound synthesized before the reaction that produces the drug substance. The final step, forming the new drug substance, must involve covalent bonds. The formation of simple esters or ionic bonds does not qualify as the final synthetic step. When the drug substance is a salt, the precursors to the organic acid or base should be considered the final intermediate. There may be more than one final intermediate depending on the nature of the synthesis.
The Committee for Medicinal Products for Human Use (CHMP) Guidance on the Chemistry of New Active Substances notes that a starting material is incorporated as a significant structural fragment into the structure of a drug substance and marks the beginning of the detailed description of the drug substance synthesis (9). Starting materials with a Certificate of the European Pharmacopoeia (CEP) or subject of an approved MAA are acceptable. An MAA requires the following:
The EU GMP Annex 18 adopted the ICH Q7 definition of a starting material (10). Table I of this document provides guidance on where CGMP is applied to a synthetic process.
The European Directorate for the Quality of Medicines (EDQM) Public Document, in noting the top 10 deficiencies in Certificate of the European Pharmacopoeia (CEP) applications, identifies the lack of detailed information about the synthesis of starting materials, and impurity carry over has been highlighted as the number one deficiency (11).
MHLW guidance. The Japanese MHLW Notification PFSB/ELD 020001 indicates starting materials should be based on the ICH Q7 definition (PAB notification number 1200, Nov. 2, 2001) (12). The starting material justification should be described in CTD Section 3.2.S2.6 and include the criteria for the starting materials and the name, principle, and outline of testing methods.
The applicant should start the description of the manufacturing process from a step that is necessary for ensuring drug-substance quality. The guidance defines a final intermediate and notes that a registered synthesis should include more stages than the final stage.
From the standpoint of risk control, the manufacturing process stated in the application should include processes that are essential for ensuring drug-substance quality. Manufacturing parameters or charged quantities should be identified according to whether they can be subsequently changed by prior approval (partial change application, PCA) or by a minor amendment (Notification). Changes to the reaction process, including starting materials, or a change of specification or test method if likely to impact on quality of drug substance requires prior approval (i.e., PCA).