General Principles & Practices

What is process equipment?

• The manufacturing of biotechnological-derived medicinal products involves several process steps from upstream to downstream operations. Various process equipment is used for the bioprocessing of biopharmaceuticals and immunotherapies.
• The process equipment varies from standard to complex equipment and devices used for production. Equipment used in a GMP-related environment should be suitable and should not present any hazard to the product. The location and installation of the equipment should be adequate to minimize risk and contamination.

Why is equipment qualifcation necessary?

• The objective of process equipment qualification is to verify the fitness for purpose for its intended use and to ensure that process equipment meet their specifications as devised in the URS.

Implementation of equipment qualification

• The qualification process outlined in the qualification plan include URS, risk assessment, and lifecycle management.
• Process equipment should be qualified according to the Qualification Phases (DQ, IQ, OQ, PQ), calibrated, inspected and maintained at defined intervals to ensure adequate performance. Associated computerized systems (CS) should be validated to verify data integrity and data security.

When is qualification needed?

• Regulatory compliance with Good Manufacturing Practice (GMP)
• New equipment installation
• Equipment modification
• Maintenance or repair
• Change in the manufacturing process

General Principles and Practices

Why Process Validation Studies?

• Process validation studies verify that the manufacturing process is under control and operates within defined specifications. Process validation contributes to confidence in product and process quality and ensures compliance with GMP to receive the manufacturing authorization.
• Validation studies apply to drugs, biologicals, drug substances, or active pharmaceutical ingredients. The strategy to process validation should be laid down in a process validation plan.
• Current scientific knowledge and the accumulated data collected during drug and preclinical development, quality control and manufacturing processes should be included to the validation studies.

Product Characterization

• The objective of product characterization is to contribute to a better knowledge of product-biology and structure-function relationships. The biological product is characterized by its biological, physico- and immunochemical properties, and by purity and impurities.
• However, the assessment of biological properties plays a major role in establishing a characterization profile. When defining critical product quality, these properties add quality characteristics and support product safety.
• Product characterization analysis are mandatory GMP requirements for release and marketing authorization according to ICH Q6B.

Risk Assessment and Lifecycle Approach

• The risk assessment identifies and provides scientific knowledge about potential quality risks. Quality risks associated with biotechnological-derived products are highly dependent on the manufacturing process, the protein itself and the manufacturing facility and environment.
• The assessment shall follow the impact of potential risks in terms of critical process parameters (CPPs) and critical quality attributes (CQAs) and applies over the product and process lifecycle.

Methods and Principles

About Computerized System Validation (CSV)

• Manufacturing facilities, analytical instruments, devices and utilities used for quality control, drug manufacturing or drug development are these days mostly combined with computerized systems. A computerized system (CS) describes a hardware with software combined applications. According to GAMP 5, the software is categorized into groups to determine the scope of validation.

GMP Compliance with CSV

• IT-Infrastructure is subject to validation regarding a GMP-related environment. CSV principles include GMP regulations e.g. FDA 21 CFR Part 11, GAMP 5, EudraLex Vol. 4 Annex 11, EudraLex Vol. 4 Annex 15, Datatype, ALCOA+ principles, and a risk-based system classification. CSV verifies that computerized system functions reliably and satisfying regulatory GMP requirements throughout the system lifecycle.

User Requirement Specification (URS)

• User requirements, system specifications and laboratory needs should be specified in the User Requirements Specification (URS). Validation specifications and the associated acceptance criteria should be established on a risk basis.

Software Categories

• Due to a variety of software applications, from firmware, infrastructure software, non-configured and configured products to custom applications, the software is classified. According to GAMP 5, the software is categorized into groups to determine the scope of validation.

Integrated Qualification

• Instrument and process equipment qualification follow an integrated approach which combines the qualification phases (DQ, IQ, OQ, PQ) into CSV. The purpose to combine CSV and system qualification is to save time and effort.

System Classification

• To determine the extent of qualification the systems are classified into categories depending on their complexity and the criticality on its intended use.

Group A

• Group A includes the simplest standards devices and instruments such as magnetic stirrer or vortex mixer which are used without measurement capability. Their handling is simple and self-explanatory. The quality of product and process will not be affected by this category and therefore qualification activities require only the basics.

Group B

• Group B includes instruments which are more complex and provide a measurement capability or a condition that may affect a measurement, for example a pH meter and oven or incubator. These instruments may have firmware but are not software-controlled. The extent of qualification activities depends on criticality regarding critical quality attributes (CQAs) and critical process parameters (CPPs) which shall be analyzed by a risk assessment.

Group C

• Group C includes complex analytical instruments with software-controlled measurements and analysis such as HPLC, mass spectrometer or flow cytometer. This category requires the highest quality standards. Their qualification is elaborate and labor-intensive. It also includes the computerized software validation (CSV) which is even more challenging and demanding.

Methods & Applications

• General applications of biological assays include characterization of biological properties, as describe in ICH Q6B, to support stability and comparability studies, batch release of samples, and to evaluate changes in manufacturing processes. Bioassays can be cell-based or cell-free. Cell-based assays refer to the use of living cells for the analysis.

Cell-based Assays

• Cell-based bioassay using cell lines, derived from tumors, immortalized cells or created by cell line engineering, to study cellular response to the protein of interest. The cellular response depends on the mode of action of the desired protein.
• Such responses include cell proliferation assays, apoptosis assays, cytotoxicity assays, or antibody-dependent cellular cytotoxicity assays (ADCC).

Potency Assays

• The objective of potency assays is the determination of the relative potency, in which the biological activity of an analyte is analyzed by comparing the dose-response curve to the activity of a reference standard material.

ADCC Assays

• Antibody-dependent cellular cytotoxicity assays.

Assays for Drug Screening and Target Validation

• Drug receptor interactions play an important role in drug delivery, tumor metastasis, and immune response. Assay development has become a powerful tool for drug screening and target validation studies as part of drug discovery and drug development.