Principles for Establishing Quality Standards
The definition of quality standards encompasses a comprehensive list that includes testing procedures, reference analytical methods, and explicit acceptance criteria. Acceptance criteria are delineated by specific limits, defined ranges, or other precise parameters describing the test attributes. These quality standards are designed to establish mandatory acceptance guidelines corresponding to the intended use for raw materials, final products, and other materials employed during the production phases. The phrase "compliance with quality standards" specifically refers to raw materials and final products meeting the predetermined acceptance criteria upon rigorous testing as per the specified analytical methods.
Quality standards, serving as crucial specifications for product quality, are proposed and validated by the manufacturer. Subsequently, these standards require review and approval by regulatory authorities as a prerequisite for product market authorization. They are a core component of the overall control strategy ensuring product quality and consistency. This comprehensive control strategy also includes extensive product characterization during the development phase to establish multiple quality standard parameters, production according to Good Manufacturing Practices (GMP), validated manufacturing processes, raw material testing, in-process control testing, and stability testing.
It is important to note that the purpose of quality standards is not to fully characterize the raw materials and formulations but to focus on the confirmed molecular structures and biological properties that are critical to ensuring product safety and efficacy. Therefore, the following principles should be adhered to when formulating quality standards: a thorough consideration of quality attribute analysis, physicochemical properties, biological activity, immunochemical properties, purity, impurities, contaminants, and content.
Analysis of Quality Characteristics
Accurate establishment of quality standards for biotechnological products and biopharmaceuticals relies significantly on appropriate techniques for their quality characteristic analysis. These analyses should encompass detailed verification of physicochemical structural features, biological activity, immunochemical properties, purity, and impurities. Setting and validation of acceptance criteria must be based on comprehensive considerations of preclinical and/or clinical batch data, batch-to-batch consistency studies, stability data, and related developmental stage data. Thorough analysis of quality characteristics is imperative during significant process changes in product development. When submitting for approval, products should be compared against reference standards where available, and where feasible, against corresponding natural components. Manufacturers should establish internal reference materials subjected to adequate quality characteristic analysis for biological and physicochemical testing upon submission for approval. Given continual advancements in analytical technologies, ongoing optimization of existing methods should be reasonably adopted to support quality analysis practices. (Adapted from ICH Q6B)
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Physical-Chemical Properties
Verification of the structural physical-chemical properties of target products typically includes steps such as component determination, physical property analysis, and primary structure determination. In specific cases, higher-level structural information of the target product (its reliability inferred through biological activity) can be obtained through appropriate physicochemical methods. Due to inherent heterogeneity in protein systems synthesized biologically, structural heterogeneity is inevitable. The target product may contain mixtures of anticipated post-translational modification forms (e.g., glycoproteins), which may possess activity, with their presence not necessarily adversely affecting product safety and efficacy. Manufacturers should delve into the heterogeneity spectrum of the target product and validate consistency across preclinical and clinical study batches. If confirmed that heterogeneity types remain constant per batch, individual assessment of each isoform's impact on product activity, efficacy, safety (including immunogenicity) may not be necessary. Heterogeneity can also arise during production or storage of raw and finished products. Given its critical impact on product quality, identification of heterogeneity degree and type ensures consistency between batches. Variants of the target product equivalent in activity, efficacy, and safety should be considered related substances. Evaluation of changes resulting from process modifications or product degradation causing inconsistency in heterogeneity profiles compared to those used in preclinical and clinical development should be assessed for impact. As analytical techniques advance and existing methods improve, their reasonable adoption at appropriate junctures is warranted. Simultaneously, appropriate methods selected from product structure verification methods should be applied to batch release testing and comprehensively discussed for their rationale. (Adapted from ICH Q6B)
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Biological Activity
Evaluation of biological properties is equally crucial as comprehensive structural verification in product assessment. Biological activity describes the specific capability or potency of a product to achieve anticipated biological effects, representing a critical characteristic of the product. Manufacturers should provide effective biological assay methods for assessing biological activity. Examples include methods such as animal-based assays, which measure biological organism responses to the product; cell-based assays, which assess biochemical and physiological effects at the cellular level; and biochemical methods, which measure biological activity through enzyme reaction rates or immunoreactivity-induced biological responses. Ligand/receptor binding assays and other suitable methods may also be acceptable. Potency (expressed in units) quantitatively determines product biological activity using attributes associated with biological properties, whereas quantity (expressed in mass) assesses protein content using physicochemical methods. Simulating biological activity identical to clinical conditions is sometimes unnecessary, but establishing correlation between expected clinical responses and biological assay activity is essential in pharmacology and clinical research. When feasible and appropriate, biological activity assay results should be calibrated in activity units against international or national reference standards. In absence of such standards, internal reference materials with quality characterization should be established, with results expressed in internally defined units for each batch. Typically, extensive physicochemical data alone for complex molecules may not determine their higher-order structure, necessitating inference from product biological activity when used in conjunction with specific quantitative detection methods with broad confidence limits, which may be acceptable. Substituting biological assays with physicochemical methods for quantifying product biological activity must fulfill the following conditions: full establishment of the product's higher-order structure using physicochemical methods and demonstration of correlation with biological activity; and establishment of comprehensive production history records. When quantifying biological activity solely through physicochemical methods (based on appropriate correlation), results should be expressed in terms of mass. For product release testing, manufacturers should determine quantitative detection methods (biological and/or physicochemical) and justify their rationale. (Adapted from ICH Q6B)
Immunological Properties
Comprehensive characterization of immunological properties is essential when dealing with antibody products. Where feasible, assays should be conducted to assess binding affinity, avidity, and immunoreactivity (including cross-reactivity) between antibodies and purified antigens or antigen-specific regions. Additionally, biochemical methods should be employed, where feasible, to identify antigenic epitopes and target molecules bearing relevant antigenic epitopes. For certain raw and finished products, immunological methods utilizing antibodies capable of recognizing different epitopes of the protein molecule (e.g., ELISA, Western Blot) are necessary to detect the protein. Immunological properties of proteins can be employed for product identification, homogeneity or purity assessment, and quantification. If immunological characteristics are utilized as release testing criteria, all pertinent antibody-related documentation should be provided. (Adapted from ICH Q6B)
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Purity
Determining absolute and relative purity poses significant challenges for analytical methods, as purity assessment outcomes heavily depend on the chosen analytical approach. Historically, relative purity of biopharmaceuticals has been expressed as specific activity (units of biological activity per milligram of product), which also varies based on the method employed. Therefore, a combination of methods is typically utilized to assess the purity of both raw materials and finished products. Given the molecular characteristics and unique biosynthetic processes of biotechnological products and biopharmaceuticals, raw materials may contain various molecular entities or variants. If these entities arise from expected post-translational modifications, they should be considered integral parts of the anticipated product. Variants formed during production and/or storage processes that exhibit properties comparable to the anticipated product should be regarded as related substances rather than impurities. When applicable, specific and/or aggregate acceptance criteria should be established for related substances. For batch release testing, a suitable set of purity determination methods should be selected, and the rationale behind their use clearly articulated. (Adapted from ICH Q6B)
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Impurities
In addition to evaluating the purity of raw materials and finished products, which may consist of anticipated products and various related substances, manufacturers are also required to assess potential impurities. Impurities can originate from manufacturing processes or from the product itself. The structure of impurities may be known, partially identified, or unidentified. Whenever feasible, efforts should be made to identify these impurities adequately, and where permissible, assess their biological activity. Process-related impurities refer to those generated during production processes, such as cell substrates (host cell proteins, host cell DNA), cell culture components (inducers, antibiotics, or culture medium ingredients), or downstream process impurities. Product-related impurities (such as precursors or certain degradation products) are molecular variants formed during production and/or storage processes, which do not possess comparability in terms of activity, efficacy, and safety with the anticipated product. Furthermore, acceptance criteria for impurities should be established based on data from preclinical and clinical study batches, as well as studies on production consistency verification batches. Separate and/or cumulative acceptance criteria should be set for product-related and process-related impurities. In certain instances, specific impurities may not necessitate acceptance criteria. (Adapted from ICH Q6B)
Contaminants
In the case of the complex antibody fusion protein, denosumab, it contains 29 disulfide bonds and various forms of mismatched disulfide bonds. Product contaminants refer to exogenous substances introduced unintentionally during non-production process expectations, such as chemical and biochemical substances (microbial proteases) and/or microbes. Contaminants should be strictly avoided, and/or appropriate process control acceptance criteria or action limits for raw materials or finished products should be implemented to control them. For exogenous viral and mycoplasma contaminants, action limits are no longer applicable, and considerations should be given to principles outlined in two ICH guidelines: "Viral safety evaluation of biotechnology products derived from human or animal cell lines" and "Characterization and qualification of cell substrates and other biological materials used in the production of biotechnological products and biopharmaceuticals." (Adapted from ICH Q6B)
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Content
The determination of antibody molecular higher-order structures commonly utilizes circular dichroism spectroscopy. This method analyzes structure by exploiting protein circular dichroism, where asymmetrical molecules absorb left and right circularly polarized light differently. Far-ultraviolet (190-230 nm) spectra reflect protein secondary structures, including α-helices, β-sheets, turns, and irregular coils. Near-ultraviolet (250-350 nm) spectra reveal changes in protein tertiary structure, indicating the distribution of chromophoric residues like tryptophan, tyrosine, and tyrosine, and variations in disulfide bond microenvironments. Additionally, differential scanning calorimetry, hydrogen-deuterium exchange mass spectrometry, Fourier-transform infrared spectroscopy, X-ray crystallography, and nuclear magnetic resonance techniques are also commonly employed to analyze the advanced structures of antibody drugs. (Adapted from ICH Q6B)
Issues Related to Analytical Methods
Reference Standards and Reference Materials
In the registration applications for new molecular entities, obtaining international or national reference standards for comparison is generally impractical. Therefore, manufacturers are required to establish primary internal reference standards through quality characterization analysis. These internal primary reference standards should be prepared using representative batches that can adequately represent samples intended for production and clinical research. Internal working reference standards used for batch testing of products should be standardized against these primary reference standards. If suitable international or national reference standards are available, they should be utilized for standardizing reference materials wherever possible. While using a single reference material for both biological and physicochemical testing is ideal, separate reference materials may sometimes be necessary.
Additionally, separate reference standards may need to be established for product-related substances, product-related impurities, and process-related impurities. If applicable, details regarding the manufacturing and/or purification methods of these reference materials should be provided during the application process. Information concerning the quality characterization analysis of reference materials, storage conditions, and formulation prescriptions used to ensure their stability should also be included.
Validation of Analytical Methods
When submitting data to regulatory authorities, in addition to specific requirements for biotechnological products and biologicals testing methods, validation of analytical methods used in quality standards should follow the principles outlined in ICH guidelines "Validation of Analytical Procedures: Definitions and Terminology" and "Validation of Analytical Procedures: Methodology." (Adapted from ICH Q6B)
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