7 Quality Considerations for Large Molecule Product Development
Posted by Dr. Theo Kapanadze, D.Sc., Ph.D on Thu, Mar 31, 2011
Biologic drugs are complicated products that are normally difficult to define in molecular terms and that can be inconsistent in their exact composition. This can make it difficult to assure product quality and therefore to ensure safety and efficacy.
Quality for biologics requires an essential appraisal for Corporate Management and those in the Product, Process and Analytical Development, Product Quality and Characterization, R&D, and Regulatory Affairs groups. It is aimed at biotechnology companies, global bio/pharma companies, producers of biosimilars and biogenerics, Contract Development and Manufacturing Organizations, manufacturing and analytical equipment suppliers, regulatory agencies and Clinical Research Organizations.
This 7 points below highlight the issues surrounding quality for biologics, their implications for the market and for the entire bio/pharmaceutical industry.
1. Critical Quality Attributes:
- Aspects of a biological that may impact function and safety
- Impact of the process on the product
- Setting the specifications
2. Bioassays for Lot Release and Comparability:
- Comparability, product lifecycle management and regulatory guidelines
- Well characterized biologicals and specified biotechnology products
- Heterogeneity of biopharmaceutical products and physicochemical testing
- Evolution in physicochemical characterization during development
- Physicochemical characterization and bioactivity
- Physicochemical lot release testing
- Biological activity, potency, functional assays
- Selection of appropriate bioassay systems
- Types of functional bioassay system
- Binding assays
- Immunoassays
- Bioassays and unwanted immunogenicity
- Assay variability, reference standards and relative potency
- Assay Design
- Assay precision
- Surrogate potency assays
3. Impact of Formulation Design on Stability and Quality:
- How the choice of excipient can affect quality
- Precautions regarding the use of animal derived materials
- Potential impact of preservatives and anti-oxidants
- Container closures, extractables and leachables: current thinking and recommended precautions
- How to ensure stability of the product in the formulation
- Robustness of formulation development studies
- Potential for improved formulations to affect the critical quality attributes
- Regulatory issues with optimizing formulation
- Factors affecting product stability
- Genetic stability
- Methods for stability testing
- Application of analytical technologies to engineer a product with greater stability
- CH guidelines on stability testing
4. Specifications and Drug Substance for Lot Release:
- EU and US perspectives on setting specifications
- Setting the specifications (acceptance criteria) and the action limits (critical product quality attributes) for quality control for specific products
- How specification requirements tighten during development and how to update the package
- How design space helps with the determination of specifications, especially for generic products outside the originator product specifications
- Parametric release, i.e. real-time product release
- Methodologies that need validation
5. Impurity Profile:
The process can impact on the impurity profile and product characterization and process-related impurities.
- Nature of product and process-related impurities
- Characterization of product and process-related impurities
- Impact of impurities on product quality
6. Impact of the Process
The process can impact on aggregation and technologies for aggregation analysis interventions in the protein secretory pathway.
- Disulphide bond formation
- Chaperones
- Multiple gene activators
- Environmental conditions
- Analytical methods to detect misfolding and aggregation
7. Importance of Non-Clinical Testing:
- In vitro systems
- In vivo systems
- Pharmacokinetics
- Toxicology studies
- Non-clinical testing in bio/pharmaceutical development
There is no perfect solution and the commercial cost of quality is high, but the cost of getting it wrong can be considerably greater or even disastrous. Considerable time and expense can be saved by having an educated approach to manufacturing and process development, characterization and analytical methods, product variation and also to regulatory strategy.
Biologic drugs are complicated biological products that are normally difficult to define in molecular terms and that can be inconsistent in their exact composition. This can make it difficult to assure product quality and therefore to ensure safety and efficacy.
There is no perfect solution and the commercial cost of quality is high, but the cost of getting it wrong can be considerably greater or even disastrous. Considerable time and expense can be saved by having an educated approach to manufacturing and process development, characterisation and analytical methods, product variation and also to regulatory issues.
Quality for Biologics is essential appraisal for corporate management and those in product, process and analytical development, product quality and characterisation, R&D, and regulatory affairs. It is aimed at biotech, big pharma, producers of biosimilars / biogenerics /, contract manufacturers, and providers of analytical services, providers of manufacturing and analytical equipment, regulatory agencies and clinical research organizations. This bulletpoints bellow highlights of the issues surrounding quality for biologics, its implications for the market and for the biotech and pharmaceutical industries.
Critical quality attributes:
- Aspects of a biological that may impact function and safety
- Impact of the process on the product
- Setting the specifications
Bioassays for Lot Release and Comparability
- Comparability, product lifecycle management and regulatory guidelines
- Well characterised biologicals and specified biotechnology products
- Heterogeneity of biopharmaceutical products and physicochemical testing
- Evolution in physicochemical characterisation during development
- Physicochemical characterisation and bioactivity
- Physicochemical lot release testing
- Biological activity, potency, functional assays
- Selection of appropriate bioassay systems
- Types of functional bioassay system
- Binding assays
- Immunoassays
- Bioassays and unwanted immunogenicity
- Assay variability, reference standards and relative potency
- Assay Design
- Assay precision
- Surrogate potency assays
Impact of Formulation Design on Stability and Quality
- How the choice of excipient can affect quality
- Precautions regarding the use of animal derived materials
- Potential impact of preservatives and anti-oxidants
- Container closures, extractables and leachables: current thinking and recommended precautions
- How to ensure stability of the product in the formulation
- Robustness of formulation development studies
- Potential for improved formulations to affect the critical quality attributes
- Regulatory issues with optimising formulation
- Factors affecting product stability
- Genetic stability
- Methods for stability testing
- Application of analytical technologies to engineer a product with greater stability
- CH guidelines on stability testing
Specifications and Drug Substance for Lot Release
- EU and US perspectives on setting specifications
- Setting the specifications (acceptance criteria) and the action limits (critical product quality attributes) for quality control for specific products
- How specification requirements tighten during development and how to update the package
- How design space helps with the determination of specifications, especially for generic products outside the originator product specifications
- Parametric release, i.e. real-time product release
- Methodologies that need validation
Impurity Profile: How the Process can Impact on the Impurity Profile, and Characterization of Product and Process Related Impurities
- Nature of product- and process-related impurities
- Characterization of product- and process-related impurities
- Impact of impurities on product quality
Impact of the Process on Aggregation, and Technologies for Aggregation Analysis Interventions in the protein secretory pathway
- Disulphide bond formation
- Chaperones
- Multiple gene activators
- Environmental conditions
- Analytical methods to detect misfolding and aggregation
Importance of Non-Clinical Testing
- In vitro systems
- In vivo systems
- Pharmacokinetics
- Toxicology studies
- Non-clinical testing in (BIO)pharmaceutical development