Specifications: Testing Procedures And Acceptance Standards For New Drug Substances And Products: Chemical Substances:

INTRODUCTION: Specifications

1.1 Purpose of the Guideline

Specifications : This guideline is designed to support the development of a unified set of global specifications for new drug substances and products. It offers direction on establishing and justifying acceptance criteria and selecting test methods for new synthetic chemical drug substances and their associated products, particularly those that have not been previously registered in regions such as the United States, European Union, or Japan.

1.2 Background

A specification is defined as a series of tests, references to analytical methods, and applicable acceptance criteria, such as numerical limits or other standards for these tests. It defines the criteria a drug substance or product must meet to be deemed acceptable for its intended use. Conformance to specifications means that when tested using the listed methods, the substance or product will meet the outlined criteria. Specifications play a crucial role as quality standards that are proposed by manufacturers and validated by regulatory authorities as part of the approval process.

They are an essential part of a broader quality control strategy, which includes product characterization, adherence to Good Manufacturing Practices (GMP), and various forms of testing such as raw material testing, stability studies, and in-process controls. The goal is to verify the quality of the drug substance and product rather than to fully characterize them.

1.3 Scope of the Guideline

This guideline covers specifications for drug substances and products, which include the tests, methods, and criteria that ensure the product’s quality at release and throughout its shelf life. While specifications are key to quality assurance, they are just one element of a comprehensive quality control approach. This document addresses only the marketing approval of new drug products (including combination products) and new drug substances. It does not apply to substances or products in clinical research. This guideline primarily applies to synthetic and semi-synthetic antibiotics and low-molecular-weight peptides but does not cover biotechnological or biological products, radiopharmaceuticals, herbal medicines, or crude animal/plant-derived products.

The guideline can also be extended to include other dosage forms, such as inhalation products, topical formulations, and transdermal systems, though these are not specifically discussed here.

GENERAL PRINCIPLES

The following concepts are essential when developing harmonized specifications. Although these may not apply universally, each should be considered based on the specific context of the drug substance or product. Any implementation of these principles should be justified and approved by the relevant regulatory bodies.

2.1 Periodic or Skip Testing

Periodic testing involves performing specified tests on selected batches or at predefined intervals instead of conducting tests on every batch. This method may be used for tests such as residual solvents or microbiological assessments in oral dosage forms. However, it must be justified and approved by regulatory authorities, and any failure to meet criteria during periodic testing should be reported.

2.2 Release vs. Shelf-life Criteria

Different acceptance criteria may be applied at release versus during shelf life for drug products. More restrictive criteria may be applied at release to ensure that the product remains within acceptable limits throughout its shelf life. This approach is sometimes used in the United States and Japan for internal purposes, while the European Union mandates distinct criteria for release and shelf-life.

2.3 In-process Testing

In-process tests are conducted during manufacturing to ensure consistency, but they are not part of the final batch testing. When in-process tests align with or are more stringent than release requirements, they may be used to meet specification requirements, provided validation ensures consistency from production to final product.

2.4 Design and Development Considerations

Specifications should be based on data collected during development, including stability studies and clinical trial data. Some tests may be excluded or replaced based on development results, such as microbiological testing for substances that do not support microbial growth.

2.5 Limited Data at Filing

At the time of filing, limited data may be available, and as more data is collected during production, it may be necessary to revise acceptance criteria. The focus should remain on safety and efficacy when setting initial criteria.

2.6 Parametric Release

Parametric release allows for the use of monitoring critical process parameters (e.g., temperature and pressure during sterilization) as an alternative to routine testing. This is applicable for sterilized products where precise control during manufacturing ensures sterility.

2.7 Alternative Testing Methods

Alternative procedures may be used to assess product quality if they are deemed as effective or superior to the standard methods. For example, spectrophotometric methods might be used instead of chromatographic ones if suitable for the specific product.

2.8 Pharmacopoeial References

Whenever applicable, pharmacopoeial methods should be followed, with harmonization efforts across international pharmacopoeias ensuring that methods and criteria are acceptable in all regions.

2.9 Emerging Technologies

The use of new or modified analytical technologies should be considered when they provide additional quality assurance. These technologies should be used when justified and validated.

2.10 Impact of Drug Substance on Product Specifications

Typically, drug products do not require testing for attributes related to the drug substance’s quality that have already been controlled at the substance level. For example, impurities controlled in the drug substance are generally not tested in the finished product.

2.11 Reference Standards

Reference standards are materials used in testing and validation, which are characterized for their intended use. These standards should be properly evaluated to ensure that they meet the necessary criteria for quality assurance.

GUIDELINES

3.1 Specifications: Definition and Justification

3.1.1 Definition of Specifications

A specification lists tests, references, and acceptance criteria for drug substances and products, establishing the standards for conformance. Justification for each test and criterion should be provided, referencing development data and stability studies, and considering potential manufacturing and analytical variability.

3.1.2 Justification of Specifications

When proposing specifications, the applicant must provide justification based on data from development and stability studies, process validation, and, if applicable, data from multiple manufacturing sites. The justification may include graphical representations of data for clarity, especially for assay and impurity levels.

3.2 Universal Tests and Criteria

3.2.1 For New Drug Substances

Tests for drug substances generally include:

• Description: Qualitative attributes like physical state and color.
• Identification: Tests that can differentiate closely related compounds.
• Assay: Procedures for determining the content of the drug substance.
• Impurities: Identifying and quantifying organic, inorganic, and residual solvents.

3.2.2 For New Drug Products

Tests for drug products generally include:

• Description: Physical description of the dosage form.
• Identification: Testing to confirm the identity of the drug substance in the product.
• Assay: A method to determine the product’s strength (content).

Impurities:

• Organic and Inorganic Impurities: These include degradation products, residual solvents, and any impurities resulting from the manufacturing process.
• Degradation Products: Acceptance limits must be set for both identified and unidentified degradation products, considering process impurities and their effect on the drug product.
• Residual Solvents: These must comply with the relevant guidelines, particularly the ICH guidelines.
• Testing Adjustments: If evidence shows excipient interference with a non-specific assay, a specific procedure must be applied. Similarly, degradation product testing can be reduced if it’s demonstrated that the drug substance doesn’t degrade under the given formulation and storage conditions.

Specific Tests for Drug Substances:

1. Physicochemical Properties: Tests for properties like pH, melting point, and refractive index are required. Specific measurement procedures should be followed.
2. Particle Size: This is crucial for drug substances intended for solid or suspension drug products, as it affects dissolution, bioavailability, and stability.
3. Polymorphism: Some substances exist in different forms (crystalline, solvate, or amorphous), and their identification and control may be necessary based on their impact on bioavailability or stability.
4. Chiral Substance Testing: When dealing with chiral substances, it’s necessary to control and test the enantiomeric impurity levels, typically using chiral assays.
5. Water Content: Testing for water content is critical, especially if the drug is hygroscopic or can form a hydrate.

Specific Tests for Drug Products:

1. Tablets and Capsules:
   • Dissolution Testing: For solid oral dosage forms, dissolution is typically tested to measure drug release. Acceptance criteria should be established based on bioavailability and formulation.
   • Disintegration Testing: For certain formulations, this may substitute dissolution testing, especially for formulations with rapid dissolution.
   • Hardness/Friability: Only included in the specification if they significantly affect product quality, such as for chewable tablets.
   • Uniformity of Dosage Units: Ensuring consistent mass or drug content in each dosage unit.
2. Oral Liquids:
   • Uniformity: For liquid formulations or powders for reconstitution, uniformity of dosage units (mass or drug content) should be ensured.
   • pH and Microbial Limits: The pH should fall within a justified range, and microbial limits should be set for testing (including aerobic microorganisms, yeasts, molds, and objectionable bacteria).
   • Preservative Content: For oral liquids requiring antimicrobial preservatives, specific acceptance criteria for the preservative content should be established.

Microbial Limits:

• The inclusion of microbial testing for drug substances and products is important, especially where the risk of contamination is higher.
• For solid oral dosage forms, microbial testing may be skipped based on validated manufacturing processes, but for injectable products or sterile formulations, sterility and endotoxin testing are critical.

Guidelines on Acceptance Criteria:

• Degradation Product Limits: The body of data generated during development should inform the setting of acceptance criteria. It’s important to avoid establishing overly tight criteria before sufficient data is available.
• Chiral Products: Specific guidelines are provided for chiral substances regarding enantiomeric purity, identity testing, and assay methods.
• Test for Specific Forms (e.g., Polymorphs): Testing polymorphic forms should be done sequentially, using dissolution as a surrogate when direct polymorphic testing is impractical.

Antimicrobial and Antioxidant Preservatives:

• Both types of preservatives need to meet specified concentrations to control microbial growth and preserve the product. Testing is generally required at release, although in-process testing may sometimes substitute.
• Preservative effectiveness must be demonstrated during product development, scale-up, and throughout the shelf life, typically as part of stability testing.

Extractables and Alcohol Content:

• Extractables from container/closure systems are typically tested to ensure they do not exceed acceptable limits, especially for oral solutions in non-glass systems.
• Alcohol content must be specified if declared on the product label and may be assayed or calculated.

Dissolution and Particle Size:

• Dissolution testing is required for oral suspensions and powders for resuspension to confirm proper drug release. The test may be performed as in-process testing if development data supports it.
• Particle size distribution may be included for oral suspensions to ensure consistent drug release, with criteria defined based on product performance.

For Parenteral Products:

• Uniformity of dosage, sterility, endotoxins/pyrogens, and particulate matter should be assessed for parenterals.
• Testing for preservatives, extractables, and functionality of delivery systems (e.g., prefilled syringes, autoinjectors) is critical.
• Osmolarity, particle size, and redispersibility for injectable suspensions should be controlled, especially for suspensions that settle on storage.

Stability and Testing Procedures:

• Testing procedures for attributes like preservative content, extractables, and rheological properties may be eliminated or performed as in-process tests when supported by development or stability data.
• Redispersibility for suspensions and reconstitution time for dry powders may be skipped or reduced if development data shows that consistent quality can be maintained.