August 4, 2021: Pharmaceutical Interview Questions and Answers
#ProcessValidation #ContinuedProcessVerification #ProcessQualification #QualityByDesign
Terminologies associated to process validation.
Attribute
An attribute is a physical, chemical, or microbiological property or characteristic of an input or output material.
Reference: ICH Quality Guideline Q5E
Critical Quality Attribute (CQA)
A CQA is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Reference: ICH Quality Guideline Q8 (R2)
Quality Attribute
A Quality Attribute is a molecular or product characteristic that is selected for its ability to indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents. Specifications measure a selected subset of the quality attributes.
Reference: ICH Quality Guideline Q6B
Control Strategy
A control strategy is a planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10).
Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy.
A control strategy can include, but is not limited to, the following:
Controls on material attributes (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc.);
Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps (Biotechnological/Biological Products), or order of addition of reagents (Chemical Products));
In-process controls (including in-process tests and process parameters); Controls on drug substance (e.g., release testing).
Reference: ICH guideline Q11
Continued Process Verification (CPV)
The CPV is the Stage 3 of Process Validation. The goal of this stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.
This is science and risk-based approach for collection and evaluation of information and data about the performance of the process, which will allow detecting undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control (§ 211.180(e)).
Critical process parameter (CPP):
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
Reference: ICH guideline Q8
Critical Material Attribute (CMA)
Critical material attribute (CMA) are defined as A material whose variability (physical, chemical, biological or microbiological property or characteristic of an input material) has an impact a critical quality attribute and therefore it should be monitored or controlled to ensure desired drug product quality.
Reference: http://www.rsc.org/
Design Space
The design space is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered a change. Movement out of the design space is considered to be a change, and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.
Reference: ICH guideline Q8 (R2)
Formal Experimental Design (synonym: design of experiments)
A Formal Experimental Design is a structured, organized method for determining the relationship between factors affecting a process and the output of that process.
Reference: ICH guideline Q8 (R2)
Lifecycle
Lifecycle includes all phases in the life of a product, from the initial development through marketing until the product’s discontinuation.
Reference: ICH guideline Q8 (R2)
Normal Operating Range (NOR)
The NOR is a defined range, within (or equal to) the Proven Acceptable Range, specified in the manufacturing instructions as the target and range at which a process parameter is controlled, while producing unit operation material or final product meeting release criteria and CQAs.
Reference: Process Robustness – A PQRI White Paper, Pharma. Engin. 2006.
Key Process Parameter (KPP; synonym: key operational parameter)
This is an input process parameter that should be carefully controlled within a narrow range and is essential for process performance. A key process parameter does not affect product quality attributes. If the acceptable range is exceeded, it may affect the process (e.g., yield, duration) but not product quality.
Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.
Non-Key Process Parameter (Non-KPP; synonym: non-key operational parameter)
This is an input parameter that has been demonstrated to be easily controlled or has a wide acceptable limit. Non-key operational parameters may have an impact on quality or process performance if acceptable limits are exceeded.
Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.
Process Parameter (synonym: operational parameter)
This is an input variable or condition of the manufacturing process that can be directly controlled in the process. Typically, these parameters are physical or chemical (e.g., temperature, process time, column flow rate, column wash volume, reagent concentration, or buffer pH).
Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.
Platform Manufacturing
This means the development of a production strategy for a new drug starting from manufacturing processes similar to those used to manufacture other drugs of the same type (the production for which there already exists considerable experience).
Reference: ICH guideline Q11
Process Analytical Technology (PAT)
A PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
Reference: ICH guideline Q8 (R2)
Process Performance Qualification (PPQ)
This is the second element of Process Qualification. It includes a combination of the actual facility, utilities, equipment, and trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. Batches prepared are also called ‘Conformance batches’ or ‘PPQ batches’.
Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.
Process Qualification
This qualification confirms that the manufacturing process, as designed, is capable of reproducible commercial manufacturing..
Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.
It consists of following 2 important elements:
(i) Qualification of Facility, Equipment, and Utilities
(ii) Process Performance Qualification
Process Robustness
Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality is known as process robustness.
Reference: ICH guideline Q8 (R2)
Process Validation
As per US FDA
Such validation is the collection and evaluation of data from the process design stage to commercial production, which establishes with scientific evidence that a process is capable of consistently delivering quality products.
Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.
As per EMA
Such validation comprises documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.
Reference: Draft Guideline on Process Validation, MA/CHMP/CVMP/QWP/70278/2012-Rev1; European Medicines Agency: 2012.
Prospective approach to PPQ
This indicates an approach wherein the Process Performance Qualification batches, manufactured using a qualification protocol, are released for distribution only after complete execution of the Process Performance Qualification Study
Reference: ISPE Guidance
PPQ re-verification
This indicates the repeating of a part of or a complete PPQ study in the event of changes in the process, equipment, etc. or as a recommendation of the CPV process to verify whether a process continues in a validated state of control and/or to verify that the changes do not adversely impact process characteristics and product quality or the validated state of control of the process
Reference: ISPE Guidance
Product Lifecycle
All phases of product stats from the initial development through marketing until the product discontinuation.
Process Validation Master Plan (synonym: validation master plan)
This is a document that defines the process validation scope and rationale and that contains the list of process validation studies to be performed.
Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.
Quality
This indicates the suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength and purity.
Reference: ICH guideline Q6A
Quality by Design (QbD)
This means a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
Reference: ICH guideline Q8 (R2)
Quality Target Product Profile (QTPP)
QTPP is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.
Reference: ICH guideline Q8 (R2)
Verification
Verification is a systematic approach to verify that manufacturing systems, acting alone or in combination, are fit for intended use, have been properly installed, and are operating correctly. This is an umbrella term that encompasses types of approaches to ensure that the systems are fit for the designed purpose. Other terms used are qualification, commissioning and qualification, system validation, etc.
Reference: ASTM E2500-07. Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment; American Society for Testing and Materials: 2007.
Worst Case
A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure.
Reference: EudraLex: The Rules Governing Medicinal Products in the European Union: Volume 4 Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex. 15.
Qualification and Validation; European Commission: 2014.
