Quality by Design : Critical Material attributes ,Process parameters and its linkage to Critical Quality Attributes.

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FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

This presentation - Part III in the series- deals with the concepts of critical material attributes, critical process parameters , their linage to the the critical Quality attributes of the Product and Quality Risk Management and its pivotal role in the QbD process.Concepts of control strategy are also discussed briefly.

This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.

Published in: Business, Technology

Quality by Design : Critical Material attributes ,Process parameters and its linkage to Critical Quality Attributes.

  1. 1. Risk Assessment:Linking Material Attributes and Process Parameters to Drug Product CQAsPresentation prepared by Drug Regulations – a not for profitorganization. Visit www.drugregulations.org for the latest in Pharmaceuticals. www.drugregulations.org 1
  2. 2. Product Profile  Quality Target Product Profile (QTPP) CQA’s  Determine “potential” critical quality attributes (CQAs)Risk Assessments  Link raw material attributes and process parameters to CQAs and perform risk assessment Design Space  Develop a design space (optional and not required)Control Strategy  Design and implement a control strategy Continual  Manage product lifecycle, including continual Improvement improvement www.drugregulations.org 2
  3. 3.  This presentation Part III of the series “QbD for Beginners” Product Profile covers basic aspects of ◦ Material attributes & criticality ◦ Process parameters & criticality CQA’s ◦ Linkage of CMA & CPP to critical quality attributes ◦ Risk , risk assessmentsRisk Assessments ◦ General Quality Risk Management process ◦ Risk Management methodology ◦ Overview of Quality Risk Management Design Space  FDA IR Tablet example ◦ Risk assessment of Drug SubstanceControl Strategy ◦ Excipient selection ◦ Initial Risk assessment of formulation variables Continual ◦ Process selection & Formulation development overview for the Example IR Improvement Tab ◦ Updated risk assessment of formulation variables ◦ Manufacturing process development for the example IR Tablets ◦ Initial Risk assessment of the (overall) drug product mfg process variables www.drugregulations.org 3
  4. 4.  FDA IR Tablet example Product Profile ◦ Initial RA of Pre roller compaction , blending & lubrication process variables ◦ Updated RA of Pre roller compaction , blending & lubrication process variables ◦ Initial RA of roller compaction & integrated milling process variables CQA’s ◦ Further manufacturing study based on risk assessment ◦ Updated RA of roller compaction & integrated milling process variablesRisk Assessments ◦ Final blending & lubrication process development ◦ Initial Risk Assessment of final blending & lubrication process variables ◦ Summary of final blending & lubrication process development Design Space ◦ Updated Risk Assessment of final blending & lubrication process variables ◦ Tablet compression process developmentControl Strategy ◦ Initial Risk Assessment of Tablet compression process variables ◦ Tablet compression process development Continual ◦ Updated Risk Assessment of Tablet compression process variables Improvement www.drugregulations.org 4
  5. 5.  Material: raw materials, starting materials, reagents, solvents, process aids, intermediates, APIs, and packaging and labelling materials, ICH Q7A Attribute: A physical, chemical, biological or microbiological property or characteristic Material Attribute: Can be an excipient CQA, raw material CQA, starting material CQA, drug substance CQA etc ◦ A Material Attribute can be quantified ◦ Typically fixed ◦ Can sometimes be changed during further processing (e.g. PSD– milling) ◦ Examples of material attributes: PSD, Impurity profile, porosity, specific volume, moisture level, sterility www.drugregulations.org 5
  6. 6.  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 (Q8R2) CPPs have a direct impact on the CQAs A process parameter (PP) can be measured and controlled (adjusted) ◦ Examples of CPPs for small molecule: Temperature, addition rate, cooling rate, rotation speed ◦ Examples of CPPs for large molecule: Temperature, pH, Agitation, Dissolved oxygen, Medium constituents, Feed type and rate www.drugregulations.org 6
  7. 7. • A Process Parameter is a Critical Process Parameter when it has a high impact CPP High Impact on a CQA• CPPs are responsible for ensuring the right CQA• CPPs are identified from a PP list of potential CPPs, (i.e. CQA PPs) using risk assessment and experimental work Low Impact PP www.drugregulations.org 7
  8. 8.  A material attribute or process parameter is critical when a realistic change in that attribute or parameter can significantly impact the quality of the output material www.drugregulations.org 8
  9. 9. Material Critical Quality attributes Critical ProcessAttributes CQA 1 Parameters MA 1 CQA 2 CPP 1 MA2 CQA 3 CPP 2 Understand & control the variability of Material attributes and critical process parameters to meet Product CQA’s. www.drugregulations.org 9
  10. 10. Two primary principles:The evaluation of The level of effort,the risk to quality formality andshould be based on documentationscientific knowledge of the quality riskand ultimately link management processto the protection should beof the patient commensurate with the level of risk ICH Q9 www.drugregulations.org 10
  11. 11. Systematic processes designed tocoordinate, facilitate and improve science-based decision making with respect to risk to quality ICH Q9 www.drugregulations.org 11
  12. 12. Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation unacceptable Risk Management tools Risk Communication Risk Control Risk Reduction Risk Acceptance Team Output / Result of theapproach Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 12
  13. 13.  Risk :The combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51). Risk Acceptance :The decision to accept risk (ISO Guide 73). Risk Analysis :The estimation of the risk associated with the identified hazards. Risk Assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. www.drugregulations.org 13
  14. 14.  Risk Communication: The sharing of information about risk and risk management between the decision maker and other stakeholders. Risk Control: Actions implementing risk management decisions (ISO Guide 73). Risk Evaluation: The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the significance of the risk. Risk Identification: The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem description. www.drugregulations.org 14
  15. 15.  Risk Management: The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk. Risk Reduction: Actions taken to lessen the probability of occurrence of harm and the severity of that harm. Risk Review: Review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and experience about the risk. Severity: A measure of the possible consequences of a hazard. www.drugregulations.org 15
  16. 16.  Detectability: The ability to discover or determine the existence, presence, or fact of a hazard. Harm: Damage to health, including the damage that can occur from loss of product quality or availability. Hazard: The potential source of harm (ISO/IEC Guide 51). www.drugregulations.org 16
  17. 17.  Quality attribute criticality is primarily based upon severity of harm. Does not change as a result of risk management. www.drugregulations.org 17
  18. 18.  Process parameter criticality is linked to the parameter’s effect on any critical quality attribute. It is based on the probability of occurrence and detectability. Therefore can change as a result of risk management. www.drugregulations.org 18
  19. 19.  Risk includes ◦ severity of harm, ◦ probability of occurrence, and ◦ detectability, Therefore the level of risk can change as a result of risk management. www.drugregulations.org 19
  20. 20. Use of QRM can improve the decision making processes from1. development,2. technical transfer,3. manufacturing,4. post approval changes and5. throughout the entire product life cycle www.drugregulations.org 20
  21. 21. Decision makers: Person(s) with competence and authority to make a decision  Ensuring that ongoing Quality Risk Management processes operate Management responsibility  Coordinating quality risk management process across various functions and departments  Supporting the team approachICH Q9 www.drugregulations.org 21
  22. 22. CONSIDERATIONSTeam approach Usually, but not always, undertaken by interdisciplinary teams from areas appropriate to the risk being considered e.g. ◦ Quality unit ◦ Development ◦ Engineering / Statistics ◦ Regulatory affairs ◦ Production operations ◦ Business, Sales and Marketing ◦ Legal ◦ Medical / Clinical ◦ &… Individuals knowledgeable of the QRM processes www.drugregulations.org 22
  23. 23. When to initiate and plan a QRM Process First define the question which should be answered (e.g. a problem and/or risk question) ◦ including pertinent assumptions identifying the potential for risk Then assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk ◦ Identify a leader and necessary resources ◦ Specify a timeline, deliverables and Initiate Quality Risk Management Process Risk Assessment Risk Identification appropriate level of decision making Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control for the QRM process Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 23
  24. 24. CONSIDERATIONS Should risks be assessed? 1. What might go wrong? Are there clear rules No or 2. What is the likelihood (probability) for decision making? justification needed it will go wrong? e.g. regulations 3. What are the consequences (severity)? Can you answer the risk assessment questions? No “formal RM“ Yes Yes Agree on a team “no RM“ “informal RM“ (small project)Risk assessment not required Initiate Risk assessment Select a Risk Management tool (No flexibility) (risk identification, analysis & evaluation) (if appropriate e.g. see ICH Q9 Annex I) Follow procedures Run risk control Carry out the(e.g. Standard Operating Procedures) (select appropriate measures) quality risk management process Document results, decisions and actions Document the steps Based on K. Connelly, AstraZeneca, 2005 www.drugregulations.org 24
  25. 25. Risk Assessment 3 fundamental Risk Identification questions What might go wrong? Risk Analysis What is the likelihood (probability) it will go wrong? Risk Evaluation What are the consequences (severity)?Note: People often use terms Initiate Quality “Risk analysis”, “Risk assessment” and Risk Management Process Risk Assessment Risk Identification Risk Analysis “Risk management” interchangeably Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control which is incorrect! Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 25
  26. 26. Risk Assessment: Risk Identification“What might go wrong?” A systematic use of information to identify hazards referring to the risk question or problem ◦ historical data ◦ theoretical analysis Initiate Quality Risk Management Process Risk Assessment Risk Identification ◦ informed opinions Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control concerns of stakeholders Risk Reduction ◦ Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 26
  27. 27. Risk Assessment: Risk Analysis“What is the likelihood it will go wrong?” The estimation of the risk associated with the identified hazards. A qualitative or quantitative process of linking the likelihood of occurrence and severity of harm Consider detectability if applicable Initiate Quality Risk Management Process Risk Assessment Risk Identification (used in some tools) Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 27
  28. 28. CONSIDERATIONSRisk Assessment: Risk AnalysisOften data driven Keep in mind: Statistical approach may or may not be used Maintain a robust data set! Start with the more extensive data set and reduce it Trend and use statistics (e.g. extrapolation) Comparing between different sets requires compatible data Data must be reliable Initiate Quality Risk Management Process Data must be accessible Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 28
  29. 29. Risk Assessment: Risk Evaluation“What is the risk?” Compare the identified and analysed risk against given risk criteria Consider the strength of evidence for all three of the fundamental questions ◦ What might go wrong? ◦ What is the likelihood (probability) it will go wrong? ◦ What are the consequences (severity)? Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 29
  30. 30. CONSIDERATIONS Risk Assessment: Risk Evaluation A picture of the life cycle = Risk Priority Number Probability x Detectability x Severity Can you find it? Data refers to„ Frequencyof Impact“occurences” driven by the number of trials„ Degree of belief past today future time www.drugregulations.org 30
  31. 31. Risk Control: Decision-making activity Is the risk above an acceptable level? What can be done to reduce or eliminate risks? What is the appropriate balance between benefits, risks and resources? Are new risks introduced as Initiate Quality Risk Management Process a result of the identified Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable risks being controlled? Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 31
  32. 32. CONSIDERATIONSRisk Control: Residual Risk The residual risk consists of e.g. ◦ Hazards that have been assessed and risks that have been accepted ◦ Hazards which have been identified but the risks have not been correctly assessed ◦ Hazards that have not yet been identified ◦ Hazards which are not yet linked to the patient risk Is the risk reduced to an acceptable level? ◦ Fulfil all legal and internal obligations Initiate Quality Risk Management Process Risk Assessment Risk Identification ◦ Consider current scientific knowledge & techniques Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 32
  33. 33. Risk Control: Risk Reduction Mitigation or avoidance of quality risk Elimination of risks, where appropriate Focus actions on severity and/or probability of harm; don’t forget detectability It might be appropriate to revisit the risk assessment during the life cycle Initiate Quality Risk Management Process for new risks or increased significance Risk Assessment Risk Identification Risk Analysis Risk Evaluation of existing risks Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 www.drugregulations.org 33
  34. 34. Risk Control: Risk Acceptance Decision to > Accept the residual risk > Passively accept non specified residual risks May require support by (senior) management > Applies to both industry and competent authorities Will always be made on a case-by-case basis Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 34
  35. 35. CONSIDERATIONSRisk Control: Risk Acceptance Discuss the appropriate balance between benefits, risks, and resources Focus on the patients’ interests and good science/data Risk acceptance is not ◦ Inappropriately interpreting data and information Initiate Quality Risk Management Process Risk Assessment ◦ Hiding risks from management / Risk Identification Risk Analysis Risk Evaluation competent authorities Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 35
  36. 36. Risk Control: Risk Acceptance Who has to accept risk? Decision Maker(s) ◦ Person(s) with the competence and authority to make appropriate and timely quality risk management decisions Stakeholder ◦ Any individual, group or organization that can …be affected by a risk ◦ Decision makers might also be stakeholders ◦ The primary stakeholders are the patient, healthcare professional, regulatory authority, and industry ◦ The secondary stakeholders are patient associations, public opinions, politicians (ICH Q9, definition) www.drugregulations.org 36
  37. 37. EXAMPLEA Risk Risk reduction stepAcceptance process finished1/3 Finish baseline for risk acceptance decision risk identification, risk analysis, risks evaluation, risks reduction Stakeholders No involved as appropiate? Yes Revisit All identified Initiate Quality No Risk Management Process risk assessment step risks assessed? Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Yes Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 37
  38. 38. EXAMPLE Measures/ actions needed? Yes Evaluate measures on severity, probability, detectability Check needed resources e.g. employee, moneyA RiskAcceptance No Measures / Actions appropriate? No Revisit risk reduction stepprocess2/3 Yes Other hazards Yes caused? Initiate Quality Risk Management Process Risk Assessment Risk Identification No Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Is a risk Risk Acceptance reducible? Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 38
  39. 39. EXAMPLE A Risk Acceptance process 3/3 Is a risk No reducible? Yes Revisit Accept the Advantage No Yesrisk assessment step residual risk? outweighs risk? Yes No Accept risk Risk not acceptable Sign off documentation Sign off documentation Initiate Quality Ready for communication Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 39
  40. 40. Risk Communication Bi-directional sharing of information about risk and risk management between the decision makers and others Communicate at any stage of the QRM process Communicate and document the output/result of the QRM process appropriately Communication need not be carried out for each and every individual risk acceptance Use existing channels as specified in Initiate Quality Risk Management Process regulations, guidance and SOP’s Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process According to ICH Q9 Risk Review Review Events www.drugregulations.org 40
  41. 41. CONSIDERATIONS Risk Communication Exchange or sharing of information, as appropriate Sometimes formal sometimes informal ◦ Improve ways of thinking and communicating Increase transparency Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 41
  42. 42. CONSIDERATIONS Communication facilitates trust and understandingRegulators Industryoperation operation - Reviews - Submissions - Inspections - Manufacturing www.drugregulations.org 42
  43. 43. Risk review: Review Events Review the output / results of the QRM process Take into account new knowledge and experience Utilise for planned or unplanned events Implement a mechanism to review or monitor events Reconsideration of risk acceptance decisions, as appropriate Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process ICH Q9 Risk Review Review Events www.drugregulations.org 43
  44. 44. CONSIDERATIONS System Risk (facility & people) ◦ e.g. interfaces, operators risk, environment, components such as equipment, IT, design elements System Risk (organisation) ◦ e.g. Quality systems, controls, measurements, documentation, regulatory compliance Process Risk ◦ e.g. process operations and quality parameters Product Risk (safety & efficacy) ◦ e.g. quality attributes: measured data according to specifications www.drugregulations.org 44
  45. 45. CONSIDERATIONS Supports science-based decisions A great variety are listed but other existing or new ones might also be used No single tool is appropriate for all cases Specific risks do not always require the same tool Using a tool the level of detail of an investigation will vary according to the risk from case to case Different companies, consultancies and competent authorities may promote use of different tools based on their culture and experiences www.drugregulations.org 45
  46. 46.  Supports a scientific and practical approach to decision-making Accomplishing steps of the QRM process ◦ Provides documented, transparent and reproducible methods ◦ Assessing current knowledge ◦ Assessing probability, severity and sometimes detectability Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process ICH Q9 Risk Review Review Events www.drugregulations.org 46
  47. 47.  Adapt the tools for use in specific areas Combined use of tools may provide flexibility The degree of rigor and formality of QRM ◦ Should be commensurate with the complexity and / or criticality of the issue to be addressed and reflect available knowledge Informal ways ◦ empirical methods and / or Initiate Quality Risk Management Process internal procedures Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process ICH Q9 Risk Review Review Events www.drugregulations.org 47
  48. 48.  Might be used in QRM by industry and regulators This is not an exhaustive list No one tool or set of tools is applicable to every situation in which a QRM procedure is used For each of the tools ◦ Short description & reference ◦ Strength and weaknesses ◦ Purely illustrative examples Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process ICH Q9 Risk Review Review Events www.drugregulations.org 48
  49. 49. CONSIDERATIONS Failure Mode Effects Analysis (FMEA) ◦ Break down large complex processes into manageable steps Failure Mode, Effects and Criticality Analysis (FMECA) ◦ FMEA & links severity, probability & detectability to criticality Fault Tree Analysis (FTA) ◦ Tree of failure modes combinations with logical operators Hazard Analysis and Critical Control Points (HACCP) ◦ Systematic, proactive, and preventive method on criticality Hazard Operability Analysis (HAZOP) ◦ Brainstorming technique Preliminary Hazard Analysis (PHA) ◦ Possibilities that the risk event happens Risk ranking and filtering Initiate Quality Risk Management Process ◦ Compare and prioritize risks with factors for each risk Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events www.drugregulations.org 49
  50. 50.  Supporting statistical tools ◦ Acceptance Control Charts (see ISO 7966) ◦ Control Charts (for example)  Control Charts with Arithmetic Average and Warning Limits (see ISO 7873)  Cumulative Sum Charts; “CuSum” (see ISO 7871)  Shewhart Control Charts (see ISO 8258)  Weighted Moving Average ◦ Design of Experiments (DOE)  Pareto Charts ◦ Process Capability Analysis Initiate Quality Risk Management Process Risk Assessment ◦ Histograms Risk Identification Risk Analysis Risk Evaluation Risk Management tools unacceptable Risk Communication ◦ Use others that you are familiar with…. Risk Control Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process ICH Q9 Risk Review Review Events www.drugregulations.org 50
  51. 51. Opportunities to impact risk usingDesign quality risk management Process Materials Manufacturing Facilities Distribution Patient G.- Claycamp, FDA, June 2006 www.drugregulations.org 51
  52. 52. Opportunities to impact risk using Design quality risk Q9 management Process Materials Manufacturing Facilities Distribution PatientQ8 Q10 G.- Claycamp, FDA, June 2006 www.drugregulations.org 52
  53. 53.  Valuable science-based process Can identify and rank parameters ◦ Process, ◦ Equipment, ◦ Input materials With potential to have an impact on product quality, based on ◦ Prior knowledge and ◦ Initial experimental data Performed early in the development process. Repeated as more information becomes available and greater knowledge is obtained. www.drugregulations.org 53
  54. 54.  The initial list of potential parameters can be quite extensive This can be modified and prioritized by further studies ◦ Combination of design of experiments ◦ Mechanistic models The list can be refined further through ◦ Experimentation to determine the significance of individual variables and ◦ Potential interactions Once the significant parameters are identified, they can be further studied through ◦ A combination of design of experiments, ◦ Mathematical models, or ◦ Studies that lead to mechanistic understanding Higher level of process understanding www.drugregulations.org 54
  55. 55.  QRM is an iterative process Not a one off activity Lead to a greater assurance of quality Facilitate awareness of risks Risk does not go away Risk can be predicted, prevented and controlled Determine what is important in a process & control Should be used over life cycle of the product www.drugregulations.org 55
  56. 56.  Reduce subjectivity by ◦ Multi disciplinary team ◦ Include all stakeholders ◦ Clear and consistent in wording terms ◦ Use internationally agreed definitions ◦ Transparency on the logic of the methodology and the decision making ◦ Do not be use to justify failure ◦ Use proactively for increasing the knowledge of product & processes www.drugregulations.org 56
  57. 57.  “It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/or internal procedures e.g., standard operating procedures). The use of informal risk management processes (using empirical tools and/or internal procedures) can also be considered acceptable. www.drugregulations.org 57
  58. 58.  Appropriate use of quality risk management can facilitate but does not obviate industry’s obligation to comply with regulatory requirements and Does not replace appropriate communications between industry and regulators.” www.drugregulations.org 58
  59. 59. www.drugregulations.org 59
  60. 60. Component Function Unit Unit ( mg/tablet) ( % W/W)Acetriptan, USP Active 20 10Lactose Monohydrate, NF Filler 64-86 32-43Microcrystalline Cellulose Filler 72-92 36-46(MCC), NFCroscarmellose Sodium Disintegrant 2-10 1-5(CCS), NFMagnesium Stearate, NF* Lubricant 2-6 1-3Talc, NF Glidant/Lubricant 1-10 0.5-5Total tablet weight 200 100 www.drugregulations.org 60
  61. 61. Appearance White to off-white, crystalline powderParticle Plate-like crystalsmorphologyParticle size PSD of drug substance Lot #2 was measured using Malvern Mastersizer. Thedistribution results were as follows: d10 – 7.2 µm; d50 – 12 µm; d90 – 20 µm. This is representative of the drug substance PSD selected for the final drug product formulation.Solid state • To date, three different crystalline forms (Form I, II and III) have beenform: identified and reported in the literature. • The solubility and the melting point are different for each of the three polymorphs. • Polymorphic Form III is the most stable form and has the highest melting point. • The DMF holder provides acetriptan polymorphic Form III consistently • Stress testing confirmed that no polymorphic conversion was observed and Form III is stable under the stress conditions of high temperatures, high humidity, UV light and mechanical stress. • Since it is the most stable form, no phase transformation during the manufacturing process is expected www.drugregulations.org 61
  62. 62. Aqueous 0.1 N HCL 0.015 mg/mlsolubility as a pH 4.5 buffer 0.015 mg/mlfunction ofpH: pH 6.8 buffer 0.015 mg/mlHyroscopicity Acetriptan Form III is non-hygroscopic and requires no special protection from humidity during handling, shipping or storageDensity (Bulk, • Bulk density: 0.27 g/ccTapped, and • Tapped density: 0.39 g/ccTrue) and • True density: 0.55 g/ccFlowability: • The flow function coefficient (ffc) was 2.95 and the Hausner ratio was 1.44 which both indicate poor flow properties.Chemical • pKa: Acetriptan is a weak base with a pKa of 9.2.properties • Overall, acetriptan is susceptible to dry heat, UV light and oxidative degradation.Biological • Partition coefficient: Log P 3.55 (25 °C, pH 6.8)properties • Caco-2 permeability: 34 × 10-6 cm/s. Therefore, acetriptan is highly permeable. • BCS Class II compound (low solubility and high permeability) www.drugregulations.org 62
  63. 63.  The excipients used in acetriptan tablets were selected based on ◦ The excipients used in the RLD, ◦ Excipient compatibility studies and ◦ Prior use in approved ANDA products that utilize roller compaction (RC). www.drugregulations.org 63
  64. 64.  Excipient compatibility is an important part of understanding the role of inactive ingredients in product quality. The selection of excipients for the compatibility study should be based on the ◦ Mechanistic understanding of the drug substance and its impurities, ◦ Excipients and their impurities, ◦ Degradation pathway and ◦ Potential processing conditions for the drug product manufacture. A scientifically sound approach should be used in constructing the compatibility studies. www.drugregulations.org 64
  65. 65.  To confirm its physical stability, the final drug product was sampled during lab scale studies to evaluate whether processing conditions affected the polymorphic form of the drug substance. The XRPD data showed that the characteristics 2è peaks of Form III of the drug substance are retained in the final drug product. www.drugregulations.org 65
  66. 66. Low Broadly acceptable risk. No further investigation is needed.Medium Risk is acceptable. Further investigation may be needed in order to reduce the risk.High Risk is unacceptable. Further investigation is needed to reduce the risk. www.drugregulations.org 66
  67. 67. Drug Substance AttributesDrug Solid PSD Hygrosc Solubil Mois Residual Process Chemi FlowProduct State opicity ity ture Solvent Impurit cal prop ContCQA Form ies stabili ent tyAssay Low Med Low Low Low Low Low High MedCU Low High Low Low Low Low Low Low HighDissolution High High Low High Low Low Low Low LowDegradation Med Low Low Low Low Low Low High Lowproducts www.drugregulations.org 67
  68. 68. Drug Substance Drug Product Justification Attributes CQA’s Assay Drug substance solid state form does not affect tablet assay. The risk is low. Content Drug substance solid state form does not affect tablet Uniformity CU. The risk is low. Dissolution Different polymorphic forms of the drug substance have different solubility and can impact tablet dissolution. The risk is high.Solid state form Acetriptan polymorphic Form III is the most stable form and the DMF holder consistently provides this form. In addition, pre-formulation studies demonstrated that Form III does not undergo any polymorphic conversion under the various stress conditions tested. Thus, further evaluation of polymorphic form on drug product attributes was not conducted. Degradation Drug substance with different polymorphic forms may Products have different chemical stability and may impact the degradation products of the tablet. The risk is medium www.drugregulations.org 68
  69. 69. Drug Substance Drug Product Justification Attributes CQA’s Assay A small particle size and a wide PSD may adversely impact blend flowability. In extreme cases, poor flowability may cause an assay failure. The risk is medium. Content Particle size distribution has a direct impact on drug Uniformity substance flowability and ultimately on CU. Due to theParticle Size fact that the drug substance is milled, the risk is high.Distribution Dissolution The drug substance is a BCS class II compound; therefore, PSD can affect dissolution. The risk is high. Degradation The effect of particle size reduction on drug substance Products stability has been evaluated by the DMF holder. The milled drug substance exhibited similar stability as unmilled drug substance. The risk is low. Assay Content uniformityHygroscopicity Acetriptan is not hygroscopic. The risk is low. Dissolution Degradation Products www.drugregulations.org 69
  70. 70. Drug Substance Drug Product Justification Attributes CQA’s Assay Content Solubility does not affect tablet assay, CU and Uniformity degradation products. Thus, the risk is low. Degradation ProductsSolubility Dissolution Acetriptan exhibited low (~0.015 mg/mL) and constant solubility across the physiological pH range. Drug substance solubility strongly impacts dissolution. The risk is high. Due to pharmaceutical equivalence requirements, the free base of the drug substance must be used in the generic product. The formulation and manufacturing process will be designed to mitigate this risk.Moisture Assay Moisture is controlled in the drug substanceContent specification (NMT 0.3%). Thus, it is unlikely to impact Content assay, CU and dissolution. The risk is low. Uniformity Dissolution Degradation The drug substance is not sensitive to moisture based Products on forced degradation studies. The risk is low. www.drugregulations.org 70
  71. 71. Drug Substance Drug Product Justification Attributes CQA’s Assay Residual solvents are controlled in the drug substance specification and comply with USP <467>. At ppm Content level, residual solvents are unlikely to impact assay, CUResidual Uniformity and dissolution. The risk is low.Solvents Dissolution Degradation There are no known incompatibilities between the Products residual solvents and acetriptan or commonly used tablet excipients. As a result, the risk is low. Assay Total impurities are controlled in the drug substance specification (NMT 1.0%). Impurity limits comply with ContentProcess ICH Q3A recommendations. Within this range, process UniformityImpurities impurities are unlikely to impact assay, CU and Dissolution dissolution. The risk is low. Degradation During the excipient compatibility study, no Products incompatibility between process impurities and commonly used tablet excipients was observed. The risk is low. www.drugregulations.org 71
  72. 72. Drug Substance Drug Product Justification Attributes CQA’s Assay The drug substance is susceptible to dry heat, UV light and oxidative degradation; therefore, acetriptan chemical stability may affect drug product assay and degradation products. The risk is high. Content Tablet CU is mainly impacted by powder flowability andChemical Uniformity blend uniformity. Tablet CU is unrelated to drugStability substance chemical stability. The risk is low Dissolution Tablet dissolution is mainly impacted by drug substance solubility and particle size distribution. Tablet dissolution is unrelated to drug substance chemical stability. The risk is low. Degradation The risk is high. See justification for assay. Products www.drugregulations.org 72
  73. 73. Drug Substance Drug Product Justification Attributes CQA’s Assay Acetriptan has poor flow properties. In extreme cases, poor flow may impact assay. The risk is medium. Content Acetriptan has poor flow properties which may lead toFlow Uniformity poor tablet CU. The risk is high.Properties Dissolution The flowability of the drug substance is not related to its degradation pathway or solubility. Therefore, the Degradation risk is low. Products www.drugregulations.org 73
  74. 74.  A risk assessment of the drug substance attributes was performed to evaluate the impact that each attribute could have on the drug product CQAs. The relative risk that each attribute presents was ranked as high, medium or low. The high risk attributes warrant further investigation The low risk attributes require no further investigation. The medium risk is considered acceptable based on current knowledge. Further investigation for medium risk may be needed in order to reduce the risk. www.drugregulations.org 74
  75. 75.  In this initial risk assessment for formulation development, the detailed manufacturing process has not been established. Thus, risks are rated assuming that for each formulation attribute that changed, an optimized manufacturing process would be established. www.drugregulations.org 75
  76. 76. Formulation VariablesDrug product DS PSD MCC/ CCS Level Talc Level Mag StearateCQA Lactose Level ratiosAssay Medium Medium Low Low LowContent High High Low Low LowUniformityDissolution High Medium High Low HighDegradation Low Low Low Low MediumProducts www.drugregulations.org 76
  77. 77. Formulation Drug Product CQA justification Variables Assay A small particle size and a wide PSD may adversely impact blend flowability. In extreme cases, poor flowability may cause an assay failure. The risk is medium. Content Uniformity Particle size distribution has a direct impact on drug substance flowability and ultimately on CU. Due to the fact that the drug substance is milled,Drug substance the risk is high.PSD Dissolution The drug substance is a BCS class II compound; therefore, PSD can affect dissolution. The risk is high. Degradation Products The effect of particle size reduction on drug substance stability has been evaluated by the DMF holder. The milled drug substance exhibited similar stability as unmilled drug substance. The risk is low. www.drugregulations.org 77
  78. 78. Formulation Drug Product CQA justification Variables Assay MCC/Lactose ratio can impact the flow properties of the blend. This, in turn, can impact tablet CU. Content Uniformity The risk is high. Occasionally, poor CU can also adversely impact assay. The risk is medium. Dissolution MCC/lactose ratio can impact dissolution viaMCC/ Lactose tablet hardness. However, hardness can beratio controlled during compression. The risk is medium Degradation Products Since both MCC and lactose are compatible with the drug substance and will not impact drug product degradation, the risk is low. www.drugregulations.org 78
  79. 79. Formulation Drug Product CQA justification Variables Assay Since the level of CCS used is low and its impact on flow is minimal, it is unlikely to impact assay Content Uniformity and CU. The risk is low.CCS Level Dissolution CCS level can impact the disintegration time and, ultimately, dissolution. Since achieving rapid disintegration is important for a drug product containing a BCS class II compound, the risk is high. Degradation Products CCS is compatible with the drug substance and will not impact drug product degradation. Thus, the risk is low. www.drugregulations.org 79

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