Robert J. Timko, PhD, is a CMC director of global regulatory affairs at AstraZeneca LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, tel. 302.886.2164, fax 302.886.1557, robert.timko@astrazeneca.com

Robert Timko

 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). 

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 

 and the withdrawal of FDA's BACPAC I and drug substance ICH guidances  (1–5). 

Figure 1: Schematic of regulatory drug substance synthesis. Steps 1â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) 

 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. 

 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. 

 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. 

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 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

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 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). 

 ICH Q8 and Q9 enable alternative approaches to the selection and justification of starting materials (2, 9). ICH Q8 defines design space as "the multidimensional combination and interaction of input variables (e.g., materials attributes) and process parameters that have been demonstrated to provide assurance of quality." Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Knowledge of the design space gained through the application of scientific approaches and quality risk management (ICH Q9) to the development of a product and its manufacturing process is shared with regulatory agencies to establish risk- and science-based controls that will be applicable throughout a product's life cycle. 

 The degree of regulatory flexibility gained through ICH Q8 and ICH Q9 is predicated on the level of relevant scientific knowledge provided. The impact can be seen when contrasting the traditional versus the design space approaches to selecting starting materials. 

The traditional approach to starting material identification and development has involved only two steps:   

Provide minimal starting material information about the level and fate of impurities 

Define and maintain tight specifications for starting material and drug substances to compensate for limited synthetic knowledge.

In contrast, the design space approach involves the following:   

Select starting materials based on scientific understanding of the drug substance synthesis and available control mechanisms 

Understand the source, formation, and fate of impurities

Understand how changes to the synthesis of the starting material may influence impurity profiles. 

This knowledge should allow for risk-based decisions regarding regulatory flexibility (e.g., a shorter synthetic route with more analytical controls, or a longer synthetic route with a reduced level of analytical controls that meet the desired quality standards). 

Although both industry and regulatory authorities have quality and patient safety at the forefront of their minds, the selection of a starting material is a balance between appropriate regulatory control and sustainable economic manufacture (see Figure 3). Often the origin of the starting material lies in a complex supply chain of both commodity and custom manufacture, to which it is not practical or economic to apply regulatory change control or CGMPs. Recently, FDA adopted a science- and risk base approach (13) to ensure control of impurities and quality attributes, resulting in some guidances being withdrawn in favor of ICH documentation.  

Figure 3: Selection of drug substance starting materials is based on a balance between regulatory requirements and manufacturing efficiency considerations. (IMAGE SOURCE/GETTY IMAGES) 

A review of global regulatory guidance and the design space concept indicates that justifications for proposed starting materials could be grouped into three themes: process control, analytical control, and change control. The successful selection of a starting material is on a case-by-case basis dependent on the balance and weight of justification of these three themes. 

Regulatory review of the starting material selection commences with the filing of the initial investigational new drug application (IND) or investigational medicinal product dossier (IMPD) to support clinical trials. In the US, agreement on starting materials is usually sought at the IND end-of-Phase II meeting, although final approval always awaits NDA approval. FDA encourages dialogue with the sponsors on starting material selection throughout synthesis development. In Europe and Japan, consultation is less common, and usually starting materials are agreed during MAA/NDA review. 

 In demonstrating process control of the registered process, the sponsor must determine whether the proposed starting material is made by means of custom synthesis or it is a commodity reagent.  

Commodity reagent starting materials are likely to have been made by well-characterized synthetic techniques in large scale and are commercially available for several industrial applications (e.g., food or speciality chemicals). As a consequence, they are unlikely to present an unexpected risk to a patient. Very limited process information is submitted to regulatory authorities in these cases because it is often very difficult to obtain proprietary information from suppliers unfamiliar with the demands of the pharmaceutical industry. 

Custom-synthesis starting materials are likely to be made by custom manufacturers and in varying scales throughout the drug's development. The sponsor must demonstrate the process has been fully developed and that further scale up will not present a risk to a patient.  

Data that would confirm a process is under control would include:  

Disclosure of sufficient synthetic stages must explain how the important structural elements are assembled into the complex drug substance.

Identification of the final intermediate in the submitted documentation not only helps the selection of the starting materials, it also clarifies significantly differing filing requirements for postapproval change in the US (changes to an approved NDA or ANDA, CANA) (8).

Detailed discussion of the fate of impurities, including potential genotoxic impurities, present in the starting material and those generated during the registered process should be addressed. Discussion of the process design space and how variation in the process affects the removal of impurities in the starting material should be included.

Complex chemistry stages (e.g., chiral synthesis, novel chemistry) should be discussed.

Articles

The authors review the current regulatory framework for the selection of drug substance starting materials.