The term starting material has been adopted to indicate the point where regulatory change control and current good manufacturing practices (CGMPs) are
introduced into the synthesis of a drug substance. A typical example of a drug substance synthesis is shown in Figure 1.
This generic scheme depicts four regulatory steps and various quality control points (specifications).
(IMAGE SOURCE/GETTY IMAGES)
Using a science- and risk-based framework, this article reviews the regulatory guidelines in the United States (US Food and
Drug Administration), European Union (European Medicines Agency, EMEA), and Japan (Ministry of Health, Labour, and Welfare,
MHLW). In addition, the authors address the International Conference on Harmonization (ICH) guidelines that currently impact
the selection of starting materials for new drug substances for global registration. The discussion takes into account the
recent guidance changes since the initial publication with the introduction of ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management and the withdrawal of FDA's BACPAC I and drug substance ICH guidances (1–5).
Figure 1: Schematic of regulatory drug substance synthesis. Steps 1–4 involve a covalent bond formation. The regulatory steps
are disclosed in the Marketing Authorization Application and require regulatory approval for changes. Boxes in red have the
greatest regulatory significance. Materials in bold text are usually given a comprehensive and robust specification. Boxes
in orange are synthetic intermediates, which can be isolated or remain in situ but are controlled using a more limited specification.
(IMAGE SOURCE/GETTY IMAGES)
ICH 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):
- It is incorporated into the new drug substance as an important structural element
- It is commercially available
- It is a compound whose name, chemical structure, chemical and physical characteristics and properties, and impurity profile
are well defined in the chemical literature
- It is obtained by commonly known procedures (this applies principally to starting materials extracted from plants and animals,
and to semi-synthetic antibiotics).
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.
Recently, FDA used the concept of a "negotiated starting material" to allow sponsors the "option" of reduced GMP demands for
early synthetic steps while retaining regulatory oversight over an extended synthesis (see Figure 2). The concept allows for
an "intermediate" as defined by current guidelines to be considered a starting material. Generally, this results in reduced
regulatory flexibility for starting material changes because longer syntheses are disclosed. However, there may be alternative
economic advantages to the sponsor company.
Figure 2: Example of a negotiated starting material for a new drug substance synthesis. (IMAGE SOURCE/GETTY IMAGES)
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:
- Fully characterized starting materials with complete specifications, including an impurity profile
- Name and address of supplier(s)
- The starting material justification (given in Common Technical Document [CTD] module 3.2.S2.3 "Control of Materials")
- A flow chart indicating the synthetic process before the introduction of the proposed starting material (see Figure 1)
- Demonstrated control of Adventitious Agents and Transmissible Spongiform Encephalopathy (TSE) if derived from animal sources.
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).
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
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).