1. Application of the principles of QbD in vaccines production Andrea Pranti

2. 1: Background 2: QbD elements for vaccines product and process development 3: Process consistency and product quality along product life cycle 4: QbD: Overview of the assessment process (commercial purpose). Application of the principles of QbD in vaccines production

3. “...quality cannot be tested or inspected into a finished product, but quality, safety and effectiveness must be designed and built into a product and its manufacturing process”. ICH-Q8 defines it as “a systemic approach to development that begins with pre-difined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk managment “ (1) Application of the principles of QbD in vaccines production Background

4. As stated in a recent guide from FDA (2) Quality by design means: Designing and developing manufacturing Process during the product development Stage to consistently ensure a predefined quality at the end of manufacturing process. Application of the principles of QbD in vaccines production Background

5. Quality by Design (QbD) principles are applied from the onset of product definition and development, and are intended to ensure the following: Product is designed to meet patient needs including safety and efficacy requirements Process is designed to consistently meet product critical quality attributes (CQAs) Critical sources of variability are identified and controlled through appropriate control strategies Process is continually monitored, evaluated, and updated to ensure that product quality is maintained throughout the product life-cycle Application of the principles of QbD in vaccines production Background

6. Application of the principles of QbD in vaccines production Process consistency and product quality along product life cycle

7. The following passage from ICH Q8 (R2) describes the QbD elements that should be included in pharmaceutical development – at a minimum: Defining the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering e.g., the route of administration, dosage form, bioavailability, strength, and stability; Identifying potential critical quality attributes (CQAs) of the drug product, so that those product characteristics having an impact on product quality can be studied and controlled; A CQA has been defined as a « phisical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desidered product quality (3) Application of the principles of QbD in vaccines production QbD elements for vaccines product and process development

8. Determining the CQAs of the drug substance, excipients etc., and selecting the type and amount of excipients to deliver drug product of the desired quality. Identification of CQAs is done through risk assessment as per the ICH guidance Q9. Selecting an appropriate manufacturing process; Defining a control strategy Application of the principles of QbD in vaccines production QbD elements for vaccines product and process development

9. Process design space As defined by ICH Q8 (R2), 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.’ The overall approach toward process characterization involves theree key steps: - risk analysis to identify parameters for process characterization - studies are deigned using DOE such that the data are amendable for use in understandig and defining the design space. study execution with analizing of results to evaluate the relevance of the parameters into the process design space. Application of the principles of QbD in vaccines production Process consistency and product quality along product life cycle

10. Control strategy is defined as a planned set of controls derived from current product and process understanding that assures process performance and product quality ( 4) The control strategy is performed with a risk assessment that takes in consideration CQA and process capability. Process validation : is an exercise to demonstrate that the process will deliver a product of acceptable quality if operated with design space life cycle managment : CQAs should be monitored to ensure that the process is performing within defined acceptable variability that served as the basis for the process disgn. Application of the principles of QbD in vaccines production Process consistency and product quality along product life cycle

11. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

12. Review the current release tests and product quality attributes to determine their impact on safety and efficacy of the product.Where there is a direct impact on safety or efficacy, these attributes are defined as critical quality attributes (CQAs) Criticality will be defined according to specific impat score values Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

13. Analytical assessment process List all the CQAs and evaluate analytical methods in relation to the CQAs. Verify gaps in terms of assay performance vs current specification ranges Input for this assessment: Analytical method validation reports & documentation related to analytical method failures -Method performance vs. current specifications -Historical data for both release and stability Review the Critical Process Parameters against the analytical tests to determine any risk areas or discrepancies between the required control limits / performance required or impact of timing on the process and the validated performance of the assay. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

14. Process parameters assessment Operational parameters are identified as critical and non-critical based on their ability to affect product critical quality attributes, if not appropriately controlled inside a predefined range. If there is a direct impact within the tested range with a low uncertainty score, the process parameters is defined as critical process parameters (CPP). CPPs variability have an impact on critical quality attribute and therefore should be monitored or controlled to ensure the process produced the desired quality. A CPP has a high risk of falling outside the design space. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

15. Determining CPPs from the identified CQAs 1 – Determine which processing steps influence the CQAs  Review the impact of each process step on every critical quality attribute.  During this process, additional critical quality attributes may be identified, which should be recorded. 2 – Determine which specific process parameters within the processing steps affect the CQAs  Score each process parameter using cause and effect scoring. 3 – Based upon the scoring, determine which process parameters are CPPs. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

16. Determining CPPs from the identified CQAs The scoring determines the criticality of the parameter: –If there is a known direct relationship between the process parameter and a critical quality attribute, the process parameter is critical. –If there are multiple relationships suspected but unknown, the parameter is probably critical and needs to be discussed. –If a relationship is suspected but unknown for one CQA, the parameter is potentially critical and needs to be discussed. –If there is no suspected or known relationships then the parameter is not critical. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

17. Review the relevant data to support the processing ranges for each CPP to determine what range is appropiate to ensure the CPP will not adverely affect and brach the CQA specification. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

18. FMEA assessment of CPPs Conduct an FMEA to determine the failure scenarios associated with each Critical Process Parameter –Score based upon severity, occurrence and detectability to calculate an overall Risk Priority number (RPN) and determine what actions are appropriate to address the main risk ScoreSeverityOccurrenceDetection 5 Direct significant impact on one or more CQAs. Product recall. Failure almost inevitable No way to detect, not tracked or alarmed 4 Impact on product quality / process performance. Critical deviation. Repeated failuresRemote chance of detection 3 Slight impact on product quality / process performance. Major deviation. Occasional failuresModerate chance of detection 2 Negligible impact on product quality / process performance. Minor deviation. Few failuresHigh chance of detection 1 No impact on product quality / process performanceFailure is unlikelyExcursion is obvious, always detected prior to impacting process Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

19. Gaps and actions  Bring together the FMEA and analytical gap assessment  Review gaps / risk areas / knowledge gaps  Review potential actions to address the gaps, categorising into importance  Assess the extent of control for each CQA in the current specification range, and define associated risk taking into account:  the impact of high risk process steps / parameters on the CQA  the analytical capability for testing the CQA  the uncertainty score (critical quality attributes with low uncertainty should be prioritized in importance) Evaluate the rationales for current CQA ranges and verify the opportunity of actions aimed at their refinement. Generated an overall prioritised action plan according to product and process output. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

20. QUALITY BY DESIGN SUMMARY better design of process and prducts reducing number of PTC reduced cost assocated to manaufacturing operations implementation of new technology to improve manufactruing without regulatory scrutiny Operation excellence robusteness of the quality system wit respect to the process perfomance and product quality monitoring. Application of the principles of QbD in vaccines production QbD: Overview of the assessment process (commercial purpose).

21. (1) ICH Q8 : Pharmaceutical Develpoment FED.reg 71(98) 2006; WWW.ICH.ORG/lob/media 4986 pdf. WWW.ICH.ORG/lob/media (2) US food and drug ADMINISTRATION.Giudiance for industry: Q10 quality system approach to pharmaceutical c GMP regulations (FDA, Rockville, MD, septemebrer 2006) US FOOD AND DRUG ADMINISTRATIONS (3) Guidance for industry : Q8 pharmaceutical develpoment, US DEPARTMENS OF Helath and human servies (FDA, rockville, MD june) Application of the principles of QbD in vaccines production References

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