And One Enantiomer

Needed for drug substance specification: -chiral identity -chiral assay -enantiomeric impurity

Needed for drug product specification: -chiral assay -enantiomeric impurity

Scheme 2 Decision tree for chiral compound resolution. Source: Courtesy of Pharmquest Corporation, Mountain View, California, U.S.A.

A specific, stability-indicating procedure should be developed to determine the content of the new drug substance. In many cases, it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantification of the impurities. In cases where use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. For example, where titration is adopted to assay the drug substance, the combination of the assay and a suitable test for impurities should be used. Assay methods clearly define the degradation products and their limits. Scheme 3 shows a decision tree for handling the degradation products in the drug substance.


Organic and inorganic impurities and residual solvents are included in this category. Scheme 4 shows a decision tree that can be used to decide the disposition of impurities in the drug substance.

Physicochemical Properties

These are properties, such as the pH of an aqueous solution, melting point/range, and refractive index. The procedures used for the measurement of these properties are usually unique and do not need much elaboration, for example, capillary melting point and Abbe refractometry. The tests performed in this category should be determined by the physical nature of the new drug substance and its intended use.

Particle Size

For some new drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bioavailability,


Scheme 3 Decision tree for disposition of degradation products. Source: Courtesy of Pharmquest Corporation, Mountain View, California, U.S.A.

and/or stability. In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided. Scheme 5 is a decision tree for the disposition of particle size variations in the drug substances.

Polymorphic Forms

Some new drug substances exist in different crystalline forms that differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In such cases, the bioavailability stability can be altered requiring choice of specific stable solid dosage forms.


Microbiological attributes are required where preparation and storage can significantly compromise microbiological quality. Scheme 7 shows a decision tree for the disposition of microbiologically related attributes.

Scheme 4 Decision tree for disposition of impurities in the drug substances. Source: Courtesy of Pharmquest Corporation, Mountain View, California, U.S.A.


The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability and bioavailability) or manufactur-ability should be discussed relative to the respective function of each excipient. Compatibility of excipients with other excipients, where relevant (e.g., combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, and releasecontrolling agents) to provide their intended functionality, and the intended drug product shelf life that is needed for performance throughout, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification. Information to support the safety of excipients, when appropriate, should be cross-referenced.

Stability Evaluation

The International Conference on Harmonization (ICH) guidelines regarding the quality of drug substances are specific and require frequent referral to keep the preformulation activities current with the regulatory requirements. The pertinent guidelines are listed in the following.

• Q1A(R2) Stability Testing of New Drug Substances and Products (Issued 11/2003, Posted 11/20/2003);

Scheme 5 Decision tree for the disposition of particle size variation. Source: Courtesy of Pharmquest Corporation, Mountain View, California, U.S.A.

• Q1B Photostability Testing of New Drug Substances and Products (Issued 11/1996, Reposted 7/7/1998);

• Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (Issued 1/2003, Posted 1/15/2003);

• Q1E Evaluation of Stability Data (Issued 6/2004, Posted 6/7/2004);

• Q3A Impurities in New Drug Substances (Issued 2/10/2003, Posted 2/10/2003);

• Q3B(R) Impurities in New Drug Products (Issued 11/2003, Posted 11/13/2003);

• Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological Products;

• Q6A ICH; Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (12/29/2000);

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