Quality by design in computer aided drug delivery system

Qbd ich guideline

1. Quality by design in pharmaceuticals AL-AMEEN COLLEGE OF PHARMACY SUBMITTED TO, PRESENTED BY, Dr.Ayesha Syed mam Nithyaa shri S Department of pharmaceutics Department of pharmaceutics Al-Ameen college of pharmacy Al-Ameen college of pharmacy

2. Contents Introduction QBT (traditional) QBD(quality by design) Objectives ICH Q8 guidelines Components ICH Q8 Guidelines Components QBD Traditional vs scientific QBD

3. INTRODUCTION The pharmaceutical industry is one of the most strictly regulated and its products are of excellent quality. There are issues suggesting that pharmaceutical development and manufacturing can be improved. Some of these issues are Batch failures Regulatory issues (FDA recalls), Implementation of new technologies (SUPAC), Defects in pharmaceutical product quality such as manufacturing process yield, scaleup etc.,

4. Traditionally Quality by testing (QBT) Meeting the pre-specified quality by regulatory requirements during the process (bulk drug testing) and after the process (end product testing). E.g., Soluble tablets should disintegrate within 3 minutes in water at 15° to 25°C (IP 2017) What is the problem with QBT? 1.Very large batches – non uniformity 2.Time to time inprocess testing is required 3.Quality testing is the only way to test final product 4.Ongoing loss

5. QUALITY BY DESIGN According to ICH Q8 (R2), Quality by Design ( QbD ) is defined as 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. Quality by Design was actually suggested by the regulatory authorities (FDA, EMA) at the beginning of the new millennium, recognizing that “quality cannot be tested into products, i.e. quality should be built in by design”.

6. OBJECTIVES To achieve meaningful product quality specifications that are based on clinical performance. To increase process capability and reduce product variability and defects by enhancing product and process design, understanding and control. To increase product development and manufacturing efficiencies. To enhance root cause analysis and post approval change management.

7. ICH Q8 GUIDELINE ICH Q8 guideline describes ' 'good practices for pharmaceutical development''. ICH Q8 describes the principle of QBD, outlines the key element and provides illustrative pharmaceutical examples. ICH Q8 guidelines suggests that those aspects of drug substances, excipients, container & closure system and manufacturing processes that are critical to product quality should be determined and control strategies are justified. Some tools are : PAT ( process analytical technology), prior knowledge, quality risk management principles etc.

8. PAT( process analytical technology) is a system for designing, analysing and controlling manufacturing through timely measurement of critical quality and performance attributes of raw materials and in- process materials and processes with goal of ensuring final product quality. PFIZER was one of the first company to implement QBD and PAT concepts .

9. COMPONENTS OF DRUG PRODUCT GIVEN BY Q8 DRUG SUBSTANCES: The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability. Eg. Solubility, water content, particle size, permeability. EXCIPIENTS: The excipients chosen, their concentration and the characteristics that can influence the drug product performance or manufacturability. Compatibility between the drug and excipients should be evaluated. FORMULATION DEVELOPMENT: A summary should be provided describing the development of the formulation including identification of those attributes that are critical to the quality of the drug product.

10. CONTAINER AND CLOSURE SYSTEM: The choice of selection of the container closure system for the commercial product should be discussed. The choice of materials and labelling for primary packaging and secondary packaging should be justified. MICROBIOLOGICAL ATTRIBUTES : The selection and effectiveness of preservative system in products containing antimicrobial effectiveness of the products that are inherently antimicrobial. COMPATIBILITY: The compatibility of the drug products with reconstitution diluents ( eg. Precipitation, stability) should be addressed to provide appropriate and supportive information for the labelling.

11. A. Quality Target Product Profile (QTPP) The QTPP is an essential element of a QbD approach and forms the basis of design for the development of the product The QTPP provides an understanding of what will ensure the quality, safety, and efficacy of a specific product for the patient and is a starting point for identifying the CQAs. For ANDAs, the target should be defined early in development based on the properties of the drug substance (DS), characterization of the RLD product and consideration of the RLD label and intendedpatient population.

12. QTPP may include: Intended use in clinical setting, route of administration, dosage form, dosage strength(s) Container closure system Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance); Drug product quality criteria (e.g., sterility, purity, stability and drugrelease ) appropriate for the intended marketed product.

13. B. Critical quality attributes (CQA) After the identification of QTPP, next step is to identify the relevant CQAs. Any attribute of dosage form which relates to SAFETY and EFFICACY .  A CQA is defined by ICH Q8 (R2) as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit or range to ensure the desired product quality” Generally CQAs are associated with raw material (drug substance, excipients), intermediated (in-process materials), and drug product. CQAs Identification may be performed on the basis of prior information and/or quality risk management (QRM) Prior information can be obtained by literature review, technology transfer, stability reports, manufacturing experience, raw material testing data, adverse event report and recalls

14. CQA depends on two parameters: Critical Process Parameter (CPP) – A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8)  Critical Material Attribute (CMA)* – A physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of output material

15. Example Approach to Identify Material Attributes and Process Parameters: Step 1: identifying product CQAs Step 2: for each product identify intermediate CQAs that impact the drug CQAs. Step 3: identify material attributes and process parameters that impact the intermediate CQA of the process step.

16. C. Quality risk management (QRM) FDA defines, QRM as a systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product lifecycle.  QRM helps in identifying the EXTENT of the impact/risk of critical material attributes (CMA) and critical process parameter (CPP) on CQAs ,therefore it is an integral part of QbD , which can eventually help to prioritizing the CQAs. FDA suggests various tools that can be used for risk analysis, among which the relevant ones are discussed below:  1.Failure mode effect analysis 2.Fault tree analysis 3.Hazard analysis and critical control points

17. CMAs examples Drug substance: Particle size, morphology (crystalline/amorphous) Ingredients: Type, amount, ratio CPPs examples Mixing: Time, impeller/chopper speed Milling: Feeder rate, milling speed and time Wet granulation: Binder addition rate and time, kneading time Compression: Precompression/compression force, rpm, speed etc.

18. Failure mode effect analysis: Failure Mode and Effects Analysis (FMEA) is a structured approach to discovering potential failures that may exist within the design of a product or process. There are Seven Steps to Developing an FMEA: FMEA Pre-Work and Assemble the FMEA Team Path 1 Development (Requirements through Severity Ranking) Path 2 Development (Potential Causes and Prevention Controls through Occurrence Ranking) Path 3 Development (Testing and Detection Controls through Detection Ranking) Action Priority & Assignment Actions Taken / Design Review Re-ranking RPN & Closure.

19. RISK PRIORITY NUMBER: Risk Priority Number  is a numerical assessment of the risk priority level of a failure mode/failure cause in an  FMEA  analysis. It helps the responsible team/individual prioritize risks and decide on the corrective actions. FMEA RPN is calculated by multiplying Severity (S), Occurrence (O) Or Probability (P), and Detection (D) indexes. Severity, Occurrence, and Detection indexes are derived from the failure mode and effects analysis: Risk Priority Number = Severity x Occurrence x Detection Severity : The severity of the failure mode is rated on a scale from 1 to 10. A high severity rating indicates severe risk. Occurrence  (or  Probability ): The potential of failure occurrence is rated on a scale from 1 to 10. A high occurrence rating reflects high failure occurrence potential. Detection : The capability of failure detection is rated on a scale from 1 to 10. A high detection rating reflects low detection capability. For example: from the  Process FMEA  of a painting process, the RPN is 120 for the failure mode of foreign body in the painting layer .

20. Software for calculating RPN: IQ/R/FMEA software X/ mea by reliasoft APIS IQ FMEA PTC Windchill quality software Excel template

21. Method 1 : Use the Excel formula. Because of the structure of the FMEA worksheet, the Severity cell is not linked one to one with the Occurrence and Detection cell, and the RPN formula needs to be created manually one by one. Method 2 : Use  FMEA Studio Add-in  inside Excel: Create a column with RPN column type inside Column Properties. RPN will be calculated automatically within a second for the whole FMEA worksheet. Auto calculation work with every failure mode and failure cause without creating a formula one by one.

22. How to evaluate Risk Priority Number? The RPN can be used to prioritize high-risk issues and determine the requirement for corrective action. After calculation, most companies prioritize risks from the highest to the lowest RPN. The team can use the Risk Priority Number to prioritize and reduce risks in the two following methods: FMEA RPN Threshold Many organizations use an RPN limit to determine which failure mode requires corrective action and which risks are acceptable. The RPN threshold is easy to use. However, using an RPN threshold may cause team members to spend excessive time trying to reduce the Detection, Occurrence, and Severity rankings for lowering the RPN. This situation sometimes places the organization and its customers in danger. To apply the RPN threshold for an Excel FMEA worksheet, you can use Conditional Formatting or simply apply Threshold evaluation for Risk Priority Setting in  FMEA Studio Add-in .

23. 2. Fault tree analysis: Fault tree analysis (FTA) offers one approach to  root cause analysis , identifying and analyzing the root of asset issues before equipment breaks down. FTA helps in manufacturing facilities, where understanding the potential causes of system failures is crucial to preventing them. Step 1: Define the undesired event. Step 2: Identify the contributing events and factors Step 3: Construct the fault tree Step 4: Gather failure data Step 5: Perform the analysis Step 6: Interpret the results Step 7: Implement improvements and monitor progress

24. FAULT TREE CONSTRUCTION: The symbols used on a fault tree diagram are called events, conditions, or states. These can occur at any point in time during system operation. Lines connect the symbols together to show how one event may lead to another until we reach the end of our line, an undesired event (known as a fault). The faults represent things that go wrong within your system. Below is an example of how these diagrams can look:

25. Event symbols Events occur when a system or process fails. The types of events that appear in fault trees have been detailed below.

26. Top event (TE): start of the failure. Intermediate events (IE): further failures down the fault tree. Basic events (BE): They sit at the bottom of the fault tree. Underdeveloped events (UE): These events don’t have enough information and are placed as a subtree. Transfer events (TE):  There are two types: Transfer-out and transfer-in events. Transfer-out has a triangle and output to the right, and transfer-in events have input on the top of the triangle. Conditional events (CE): These events happen as conditions for a type of gate called an inhibit gate. House events (HE):These types of events are used to turn an event off and on

27. Gate symbols Gates represent the various ways that failures can occur in an asset or system .

28. AND gate: This type of gate is connected to output events. The events only occur if the input events to the gate occur. Priority AND gate: This gate occurs if all the input events happen in a specific order. OR gate: This type of gate may have one or more inputs, and an output event will occur if one or more of the input events happen. XOR gate: This gate is slightly less common. An output happens only if one input element occurs. k/N or VOTING gate: This gate is similar to OR gate visually. There will be a number of input events ‘N’ and one output event ‘k.’ The output event occurs when the number of input events occurs. The exact number of inputs needs to be met to trigger this gate. INHIBIT gate: This type of gate will have an output event when all input and conditional events occur.

29. 3. Hazard analysis and critical point analysis: HACCP is a management system in which safety is addressed through the analysis and control of biological, chemical, and physical hazards from raw material production, procurement and handling, to manufacturing, distribution and consumption of the finished product. Principle 1: Conduct a hazard analysis. Principle 2: Determine the critical control points (CCPs). Principle 3: Establish critical limits. Principle 4: Establish monitoring procedures. Principle 5: Establish corrective actions. Principle 6: Establish verification procedures. Principle 7: Establish record-keeping and documentation procedures.

30. QRM Example for “dissolution” of tablet CMAs Risk Solid state High Particle size High Hygroscopicity Low Process impurities Low Flow property Low CPPs Risk Compression force High Hopper filing speed Low Ejection speed Low

31. D. Design Space ICH Q8 defines, design space as the multidimensional combination and interaction of input variables for e.g., CMAs and CPPs that have been demonstrated to provide assurance of quality .  DoE approach (factorial/RSM) can be used to establish the design space Working within the design space is not considered as 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. 

32. E. Control strategy : A control strategy can include, but is not limited to, the following: Control of input material attributes (e.g., drug substance, excipients, primary  packaging materials) based on an understanding of their impact on processability or product quality;  Controls for unit operations that have an impact on downstream processing or product quality (e.g., the impact of drying on degradation, particle size distribution of the granulate on dissolution);  In-process or real-time release testing in lieu of end-product testing (e.g. measurement and control of CQAs during processing);  A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models.

33. REFERENCES https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/ 2014 Jul; 16(4): 771–783.Published online 2014 May 23.  doi :  10.1208/s12248-014-9598-3 PMCID: PMC4070262 PMID:  24854893 . https://www.ema.europa.eu/en/human-regulatory-overview/research-development/quality-design https://www.pda.org/docs/default-source/website-document-library/chapters/presentations/australia/quality-by-design-(qbd)-overview.pdf . https://fiixsoftware.com/glossary/fault-tree-analysis/ .