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The authors review the current regulatory framework for the selection of drug substance starting materials.
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 1â4 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 guidance. 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.
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)
EMEA guidance. 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).
Selection of starting materials
Design space. 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:
In contrast, the design space approach involves the following:
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.
Process control. 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:
Analytical control. At the heart of a strong justification for a starting material is the demonstration of adequate analytical control of the registered process. This will include data about:
Quality control points are used at appropriate points in the synthetic process to confirm the level of impurities at a particular stage and to ensure patient safety. At minimum, a sponsor is likely to provide robust specifications for the starting material, final intermediate, and drug substance to demonstrate that quality is built into the drug substance synthesis. Robust specifications for key intermediates may also be proposed. Other intermediates may not require detailed specifications to ensure drug substance quality.
Specifications for starting materials are likely to include identity, assay, and organic impurities (limits for specified, unspecified, genotoxic, and total). In some cases, these specifications are supplemented with those for residual solvents, heavy metals or catalysts, and chirality.
The specifications will follow guidance from ICH Q3A R2 Impurities in New Drug Substances, Q3C Impurities: Guidelines for Residual Solvents, and Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (14–16). The control of unspecified impurities in the starting material to a level of 0.1 or 0.2% should be considered an argument for robust process control. For genotoxic impurities, consideration should be given to the threshold of toxicological concern based on short or long-term exposure (17–20). Greater analytical control could be a used to justify fewer synthetic stages subject to regulatory oversight.
Change control. Demonstration of a robust change control system covering both the sponsor's activities and those of its suppliers provides assurance that future innovation will not undermine patient safety. In-house change control programs and vendor assurance programs are a vital part of the overall control of drug substance quality. The change control mechanism should assess potential changes for their influence on critical quality attributes of the drug substance.
The starting point for the assessment of potential process modifications is the current operating conditions and analytical methods. It is essential to confirm that the analytical techniques are capable of detecting and controlling different impurity profiles that may result from a proposed change (route or process) to the starting material.
Changes to a starting material should be subject to a detailed assessment for the presence of new impurities. Industry and regulatory agencies commonly use a 0.1% threshold for the presence of new impurities in the drug substance to determine equivalence of batches made before and after the change.
The presence of new impurities in the starting material would require a determination of their fate during subsequent processing stages. Results over ICH Q3A R2 (13) thresholds in the drug substance may require toxicological assessment.
To ensure patient safety and obtain regulatory approval, a starting material for a drug substance synthesis must be justified against a set of predefined criteria as outlined by various regulatory authorities. Using a science- and risk-based approach, the authors propose that a global regulatory strategy to justify starting materials can be based on the control of three key themes, namely:
All proposed changes to starting materials and processes must be scientifically assessed using the knowledge gained from the risk-based approach. They should be managed through an appropriate internal change control mechanism that considers the effect of the change on the critical quality attributes. A key factor in this approach is that the sponsor chooses where to set the controls and constraints to ensure a high-quality drug substance while gaining meaningful regulatory flexibility.
By selecting appropriate starting materials for the synthesis of a drug substance, both the needs of patient safety and flexible economic manufacture can be satisfied.
Where a science- and risk-based development has defined a process design space, will global regulatory authorities accept that:
Graham T. Illing, PhD, is a CMC director and group manager of global regulatory affairs at AstraZeneca (Macclesfield, England). 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, firstname.lastname@example.org. Linda Billett is a CMC director of global regulatory affairs at AstraZeneca (Macclesfield).
*To whom all correspondence should be addressed.
Submitted: Jan. 25, 2008. Accepted: Feb. 29, 2008.
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1. R.J. Timko et al., "Drug Substance Starting Materials: A Regulatory Perspective on Requirements and Selection," poster presented at American Association of Pharmaceutical Scientists Annual Meeting, Nashville, TN, Nov. 2005.
2. ICH Q8 Pharmaceutical Development (Geneva, Switzerland, May 2006).
3. ICH Q9 Quality Risk Management (Geneva, Switzerland, June, 2006).
4. FDA, Guidance for Industry: BACPAC I: Intermediates in Drug Substance Synthesis; Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation, Feb. 2001, withdrawn, Fed. Regist. Notice June 1, 2006.
5. FDA, Guidance for Industry: Drug Substance: Chemistry, Manufacturing, and Controls Information, Jan. 2004, withdrawn Fed. Regist. Notice June 1, 2006.
6. ICH Q7 Good Manufacturing Guide For Active Pharmaceutical Ingredients, (Geneva, Switzerland, Aug. 2001).
7. FDA, Guidance for Industry: Guidance for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (Rockville, MD, Feb. 1987).
8. FDA, Guidance for Industry: Changes to an Approved NDA or ANDA, Rev. 1 (Rockville, MD, Apr. 2004).
9. EMEA Committee for Proprietary Medicinal Products, Guidance on the Chemistry of New Active Substances, CPMP/QWP/130/96, Rev 1 (London, England, Dec. 17, 2003).
10. EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Part II, Basic Requirements for Active Substances used as Starting Materials (Brussels, Belgium, Oct. 2005).
11. EDQM Division Certification of Substances, Public Document PA/PH/Exp. CEP/T (06) 35, "Certification of Suitability of Monographs of the European Pharmacopoeia. How Can the Content of the Applications for a Certificate of Suitability for Chemical Purity Be Improved? The Top 10 Deficiencies found in applications" (Strasbourg, France, Dec. 2006).
12. MHLW, Pharmaceutical and Food Safety Bureau, Guidelines on Mentions in Manufacturing / Marketing Approval Application Dossiers for Pharmaceuticals and Others Based on Revised Pharmaceutical Affairs Law, PFSB/ELD 020001 (Tokyo, Japan, Feb. 10, 2005).
13. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach, Final Report (Rockville, MD, Sept. 2004).
14. ICH Q3A R2 Impurities in New Drug Substances (Geneva, Switzerland, June 2006).
15. ICH Q3C Impurities: Residual Solvents (Geneva, Switzerland, Dec. 1997, and ICH Q3C Tables and Lists, Rev. 3, Nov. 2005).
16. ICH Q6A Specifications: Test Procedures and Acceptance Criteria For New Drug Substances and New Drug Products: Chemical Substances (Geneva, Switzerland, Oct. 1999).
17. L. Muller et al., "A Rationale for Determining, Testing, and Controlling Specific Impurities in Pharmaceuticals That Possess Genotoxicity," Regulatory Toxicology & Pharmacology 44, 198–211 (2006).
18. EMEA Committee for Medicinal Products for Human Use, Guideline on the Limits of Genotoxic Impurities, CPMP/SWP/5199 (London, England, June 28, 2006).
19. Code of Federal Regulations, Title 21, Food and Drugs, Volume 3, Chapter 1, Subpart B: Food Additive Safety, Section 170.39: Threshold of Regulation for Substances Used in Food-Contact Articles (General Services Administration, Revised Apr. 1, 2007).
20. D. Jacobson-Kram and T. McGovern, 'Toxicological Overview of Impurities in Pharmaceutical Products," Advanced Drug Delivery Reviews 59 (1), 38–42, 2007.