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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 …

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.

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  • 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. 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.  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.  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.  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.  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. • 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.  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. 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. 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. Systematic processes designed tocoordinate, facilitate and improve science-based decision making with respect to risk to quality ICH Q9 www.drugregulations.org 11
  • 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.  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.  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.  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.  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.  Quality attribute criticality is primarily based upon severity of harm. Does not change as a result of risk management. www.drugregulations.org 17
  • 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.  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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. CONSIDERATIONS Communication facilitates trust and understandingRegulators Industryoperation operation - Reviews - Submissions - Inspections - Manufacturing www.drugregulations.org 42
  • 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. 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. 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.  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.  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.  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. 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.  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. Opportunities to impact risk usingDesign quality risk management Process Materials Manufacturing Facilities Distribution Patient G.- Claycamp, FDA, June 2006 www.drugregulations.org 51
  • 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.  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.  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.  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.  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.  “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.  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. www.drugregulations.org 59
  • 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. 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. 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.  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.  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.  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. 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. 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. 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. 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. 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. 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. 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. 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.  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.  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. 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. 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. 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. 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
  • 80. Formulation Drug Product CQA justification Variables Assay Generally, talc enhances blend flowability. A low level of talc is not likely to impact assay and CU. Content Uniformity The risk is low. Dissolution Compared to magnesium stearate, talc has lessTalc level impact on disintegration and dissolution. The low level of talc used in the formulation is not expected to impact dissolution. The risk is low Degradation Products Talc is compatible with the drug substance and will not impact degradation products. The risk is low. www.drugregulations.org 80
  • 81. Formulation Drug Product CQA justification Variables Assay Since the level of magnesium stearate used is low and its impact on flow is minimal, it is unlikely to Content Uniformity impact assay and CU. The risk is low. Dissolution Over-lubrication due to excessive lubricant may retard dissolution. The risk is high.Magnesiumstearate level Degradation Products Though it formed an adduct with the drug substance in the binary mixture compatibility study (magnesium stearate/DS ratio 1:1), the interaction compatibility study showed that the adduct formation is negligible when magnesium stearate is used at a level representative of the finished drug product composition (magnesium stearate/DS ratio 1:10). Thus, the risk is medium. www.drugregulations.org 81
  • 82.  For DS with plate-like morphology and particle size in the micrometer range, ◦ a larger drug substance particle size improves manufacturability because it has better flow. However, for a BCS II compound like acetriptan, ◦ larger drug substance particle size may significantly decrease dissolution and negatively impact the in vivo performance. An in silico simulation was conducted to estimate the impact of the drug substance mean particle size, d50, on ◦ Cmax ratio and ◦ AUC ratio between the test product and the RLD. www.drugregulations.org 82
  • 83.  The predefined selection criterion was ◦ a mean particle size that yielded both a Cmax ratio and an AUC ratio between 0.9 and 1.11. The data indicate that a d50 of 30 µm or less met the predefined criterion and Exhibited a limited effect on the pharmacokinetic profile when compared to the RLD. www.drugregulations.org 83
  • 84.  Acetriptan is cohesive and displays poor flowability as evidenced by the ◦ compressibility index, ◦ Hausner ratio, ◦ flow function coefficient and ◦ specific energy. Poor material flow may produce tablets with high weight and content variability due to ◦ an uneven distribution of the drug substance in the blend, ◦ uneven bulk density and, ◦ eventually, uneven filling of die cavities on the tablet press. Poor acetriptan flow rules out the use of a high drug load formulation and Supports the use of a similar drug load to the RLD which is 10%. www.drugregulations.org 84
  • 85.  Initially, direct compression of the blend was performed. The blend uniformity (BU) percent relative standard deviation (% RSD) was higher than 6%. The tablet content uniformity % RSD was even higher. Therefore, direct compression was considered an unacceptable process for this formulation www.drugregulations.org 85
  • 86.  Wet granulation was excluded due to potential thermal degradation of the drug substance during drying based on the forced degradation study results. The use of wet granulation with an organic solvent was also excluded because of the desire to avoid the environmental considerations involved. www.drugregulations.org 86
  • 87.  For dry granulation by roller compaction, the powder particles of drug substance and fillers are aggregated under high pressure to form a ribbon and Then broken down to produce granules by milling before compression (tableting). The risk of drug particle segregation can be minimized. By controlling the size distribution and flow properties of the granules, the risk of poor tablet content uniformity can be reduced. Thus, dry granulation by roller compaction was selected as the process for further drug product development efforts. www.drugregulations.org 87
  • 88.  A univariate method (i.e., one-factor-at-a time (OFAT)) is acceptable in cases where there is no potential interaction between factors. Since this is often not known, a multivariate statistical design (i.e., Design of Experiments (DOE)) is often used. A sequential strategy is commonly employed when planning a DOE. Initially, a screening DOE can be used to narrow down the extensive list of factors identified during initial risk assessment to a few vital factors. Then, a characterization DOE can be used to understand the main effects and potential interaction(s) between these vital factors. When center points are included in a 2-level factorial DOE, it is possible to test if the curvature effect is significant. www.drugregulations.org 88
  • 89.  Data analysis is done by separating the curvature term from the regression model in an adjusted model. If the curvature is significant, the design should be augmented to a response surface DOE to estimate the quadratic terms. On the other hand, if the curvature is not significant, the adjusted model and unadjusted model will be similar. Finally, a verification DOE can be employed to study the robustness of the system by varying the identified critical factors over ranges that are expected to be encountered during routine manufacturing. www.drugregulations.org 89
  • 90.  Randomization, blocking and replication are the three basic principles of statistical experimental design. By properly randomizing the experiment, the effects of uncontrollable factors that may be present can be “averaged out”. Blocking is the arrangement of experimental units into groups (blocks) that are similar to one another. Blocking reduces known but irrelevant sources of variation between groups and thus allows greater precision in the estimation of the source of variation under study. Replication allows the estimation of the pure experimental error for determining whether observed differences in the data are really statistically different www.drugregulations.org 90
  • 91.  ANOVA results should accompany all DOE data analysis, especially if conclusions concerning the significance of the model terms are discussed. For all DOE data analysis, the commonly used alpha of 0.05 is chosen to differentiate between significant and non significant factors. It is important that any experimental design has sufficient power to ensure that the conclusions drawn are meaningful. Power can be estimated by calculating the signal to noise ratio. If the power is lower than the desired level, some remedies can be employed to increase the power. For example, by adding more runs, increasing the signal or decreasing the system noise. ICH Points to Consider document for guidance on the level of DOE documentation recommended for regulatory submissions. www.drugregulations.org 91
  • 92.  Formulation development focused on evaluation of the high risk formulation variables as identified in the initial risk assessment shown earlier. The development was conducted in two stages. The first formulation study evaluated the impact of the drug substance particle size distribution, the MCC/Lactose ratio and the disintegrant level on the drug product CQAs. The second formulation study was conducted to understand the impact of extragranular magnesium stearate and talc level in the formulation on product quality and manufacturability. Formulation development studies were conducted at laboratory scale (1.0 kg, 5,000 units). www.drugregulations.org 92
  • 93.  Goal of Formulation Development Study #1 Select the MCC/Lactose ratio and Disintegrant level and To understand if there was any interaction of these variables with drug substance particle size distribution. This study also sought to establish the robustness of the proposed formulation. A 2³ full factorial Design of Experiments (DOE) with three center points was used to study the impact of these three formulation factors on the response variables. www.drugregulations.org 93
  • 94.  Formulation development study # 2 Based on the results of Formulation Development Study #1, the intragranular excipients levels were tentatively finalized. However, magnesium stearate was linked to adduct formation with acetriptan during the binary excipient compatibility study . The goal of this study was to find ◦ the minimum level of extragranular magnesium stearate needed for tabletting and ◦ to evaluate if an increase in talc could compensate for a reduction in magnesium stearate. www.drugregulations.org 94
  • 95.  The level of extragranular magnesium stearate used in Formulation Development Study #1 was 1.0%. The minimum level recommended in the Handbook of Pharmaceuticals is 0.25%. Thus, the extragranular magnesium stearate level was studied between 0.3% and 0.9%. The talc level was adjusted accordingly to maintain a total of 3.5% extragranular glidant and lubricant using a two component mixture DOE. www.drugregulations.org 95
  • 96.  The formulation composition was finalized based on Formulation Development Studies #1 and #2. The MCC/Lactose ratio and the disintegrant level were finalized in the first study. In the second study, it was concluded that a minimum level of magnesium stearate is required in the formulation to prevent picking and sticking. The level of magnesium stearate in the formulation was reduced by using it in combination with talc. www.drugregulations.org 96
  • 97.  Acceptable ranges for the high risk formulation variables have been established and should be included in the control strategy. Based on the results of the formulation development studies, the risk assessment of the formulation variables is updated www.drugregulations.org 97
  • 98. Formulation VariablesDrug product DS PSD MCC/ CCS Level Mag StearateCQA Lactose Level ratiosAssay Low Low Low LowContent Low Low Low LowUniformityDissolution Low Low Low LowDegradation Low Low Low LowProducts www.drugregulations.org 98
  • 99. Formulation Drug Product CQA justification Variables Assay All tablets showed acceptable assay. The risk is reduced from medium to low. Content Uniformity The poor flow of the drug substance is mitigated by using a roller compaction process, low drugDrug substance load and fillers that have good flowability. The riskPSD is reduced from high to low. Dissolution The risk is reduced from high to low by controlling drug substance PSD and optimizing intragranular superdisintegrant. www.drugregulations.org 99
  • 100. Formulation Drug Product CQA justification Variables The risk is reduced from high to low by optimizing Content Uniformity the MCC/Lactose ratio and using a rollerMCC/ Lactose compaction processratio Dissolution The risk is reduced from medium to low because the selected filler ratio yielded tablets with acceptable friability within a wide range of tablet hardness (5.0-12.0 kP). Tablets with hardness within this range demonstrated acceptable dissolution (> 85% in 30 min).CCS Level Dissolution All tablets showed rapid disintegration. The risk is reduced from high to low.Magnesium Dissolution The risk is reduced from high to low by optimizingStearate extragranular magnesium stearateLevel Degradation Products The risk is reduced from medium to low by only using magnesium stearate extragranularly and by using talc to minimize the level of magnesium stearate needed. The stability data further demonstrated that the product was stable www.drugregulations.org 100
  • 101.  There are various approaches to process development used in the generic pharmaceutical industry. This is one of many possible examples. All QbD approaches to process development should identify the ◦ Critical material attributes (CMAs) and ◦ Critical process parameters (CPPs) for each process step. A firm may choose to do this through ◦ Reference to documented prior knowledge or ◦ Through empirical experiments on a range of process scales building toward the exhibit scale and proposed commercial scale. www.drugregulations.org 101
  • 102.  The process development of ◦ Pre-roller compaction blending and ◦ Lubrication is an example of experimentally determining CPPs when there is variation in an input material attribute. QbD emphasizes building understanding to avert failures during scale-up. The multivariate experiments described here are a step toward defining acceptable ranges for CPPs and CMAs. www.drugregulations.org 102
  • 103.  List each process step in the manufacturing process in the sequence of occurrence. List material attributes and process parameters that can potentially impact intermediate and finished product quality attributes. The material attributes of the input materials and the process parameters used at the very first process step determine the quality attributes of the output material (intermediate) produced at this step. www.drugregulations.org 103
  • 104.  Material attributes of the intermediate from this step and process parameters of the subsequent process step in the manufacturing process will determine quality attributes of the next intermediate and, eventually, those of the finished drug product. This cycle repeats until the final process step where finished drug product is manufactured and the product quality attributes are evaluated. This map is used to guide the risk assessments performed during process development. www.drugregulations.org 104
  • 105. Identify drugproduct CQAs For each process step, identify intermediate CQAs that impact drug product CQA Identify material attributes and process parameters that may impact the intermediate CQAs of the process step www.drugregulations.org 105
  • 106. Process parameters Material attributes• Blender type • Acetriptan PSD• Order of addition• Blender fill level • Acetriptan cohesiveness• Rotation speed (if variable) • Acetriptan flowability• Number of revolutions • Excipient PSD• intensifier bar (on / off) • Excipient flowability• Holding time • Excipient bulk density• Discharge method• Drum-to-hopper transfer • Excipient moisture content• Environment (temperature and RH) • Excipient lot-to-lot variability Pre-Roller Compaction Blending and Lubrication Manufacturing CQA of output process step • Blend uniformity • Blend assay • Blend bulk density • Blend flowability • Blend compressibility / compactability • Appearance • Dimensions www.drugregulations.org 106
  • 107. Process parameters Material attributes• Blend holding time prior to RC • Blend assay• Roller compactor type• Feed screw speed • Blend uniformity• Deaeration • Blend bulk density• Roller surface design • Blend flowability• Roller pressure • Blend compressibility /• Roller speed• Roller gap compactability• Environment (temperature and RH) • Compression Roller Compaction Manufacturing CQA of output process step • Ribbon thickness • Ribbon density www.drugregulations.org 107
  • 108. Process parameters Material attributes• Mill type• Blade configuration / type / orientation• Oscillation degree / speed • Ribbon thickness• Screen type • Ribbon density• Screen size• Number of recycles• Environment (temperature and RH) Milling Manufacturing CQA of output process step • Granule uniformity • Granule size distribution • Granule flowability • Granule bulk density • Assay of granule sieve cut www.drugregulations.org 108
  • 109. Process parameters Material attributes• Blender type • Granule uniformity• Order of addition • Granule size distribution• Blender fill level • Granule flowability• Rotation speed (if variable)• Number of revolutions • Granule bulk density• Intensifier bar (on / off)Holding time • Assay of granule sieve cut• Discharge method • Magnesium stearate• Drum-to-hopper transfer • specific surface area• Environment (temperature and RH Final blending & lubrication Manufacturing CQA of output process step • Blend assay • Blend uniformity • Blend bulk density • Blend flowability • Blend compressibility / compactability www.drugregulations.org 109
  • 110. Process parameters Material attributes• Press type and number of stations• Tooling design • Blend assay• Feed frame paddle speed • Blend uniformity• Feeder fill depth • Granule size distribution• Pre-compression force• Main compression force • Blend bulk density• Press speed (dwell time) • Blend flowability• Hopper design • Blend compressibility /• Hopper fill level compactability• Drop height of finished tablets• Run time• Environment (temperature and RH) Compression (Tableting) Manufacturing CQA of output process step • Appearance • Dimensions (length, width, thickness) • Weight (individual and composite) • Hardness • Friability • Content uniformity • Assay • Disintegration www.drugregulations.org • Dissolution 110
  • 111.  A risk assessment of the overall drug product manufacturing process is performed to identify the high risk steps that may affect the CQAs of the final drug product. Subsequently, the intermediate CQAs of the output material from each process step that impact the final drug product CQAs are identified. www.drugregulations.org 111
  • 112.  For each process step, a risk assessment is conducted to identify potentially high risk process variables which could impact the identified intermediate CQAs and, ultimately, the drug product CQAs. These variables are then further investigated in order to better understand the manufacturing process and to develop a control strategy to reduce the risk of a failed batch www.drugregulations.org 112
  • 113.  Previous experience with these process steps is used to determine the degree of risk associated with each process step and Its potential to impact the CQAs of the finished drug product. www.drugregulations.org 113
  • 114. Drug Pre –RC Roller Milling Final Compression blending & Compaction Blending &product lubrication LubricationCQA’sAssay Medium Low Medium Low MediumContent High High High Low HighUniformityDissolution Medium High Medium High HighDegradation Low Low Low Low LowProducts www.drugregulations.org 114
  • 115. Process Step Drug Product Justification CQA Assay Suboptimal pre-roller compaction blending and lubrication may cause variable flowability of the blend. The risk is medium.Pre-Roller Content The PSD and cohesiveness of the drug substanceCompaction uniformity adversely impact its flowability which, in turn, affectsBlending and CU. The risk is high.Lubrication Dissolution Blending process variables may impact the distribution of CCS in the blend which could impact disintegration of the granules and, ultimately, dissolution of the tablets. The risk is medium. Degradation Blending process variables are unrelated to the products degradation products of Generic Acetriptan Tablets, 20 mg. The risk is low. www.drugregulations.org 115
  • 116. Process Step Drug Product Justification CQA Assay Roller compaction is performed to improve flow, minimize segregation and enhance CU. The risk is low. Content Variability in ribbon density during processing can uniformity potentially impact the PSD of the milled granules, thus impacting flowability and, ultimately, CU. The risk isRollerCompaction high. Dissolution Density of the ribbon can impact density and plasticity of the granules, thus impacting compressibility of the granules, hardness of the tablet and, ultimately, dissolution. The risk is high. Degradation Based on experience gained from other approved ANDAs products using roller compaction, the roller temperature does not exceed 45 °C and the dwell time during roller compaction is very short. Thus, roller compaction should not impact degradation products. The risk is low. www.drugregulations.org 116
  • 117. Process Step Drug Product Justification CQA Assay The milling step controls the final granule size distribution. A suboptimal distribution may affect flow, causing variable tablet weight and assay during compression. The risk is medium. Content If milling generates excessive fines, both bulk densityMilling uniformity and flowability of the blend may be impacted. This, in turn, may impact CU. The risk is high. Dissolution A large amount of fines may impact tablet hardness and dissolution. The risk is medium. Degradation Although the screen may heat up during the milling products process, the dwell time is brief. Milling is unlikely to impact degradation products. The risk is low. www.drugregulations.org 117
  • 118. Process Step Drug Product Justification CQA Assay The granule uniformity which affects assay and CU is controlled by earlier steps (pre-RC blending and lubrication as well as roller compaction and integrated Content milling). This step is to blend the granules with small uniformity quantities of extragranular glidant and lubricant and isFinal unlikely to impact assay and CU. The risk is low.Blending & Dissolution Over-lubrication due to an excessive number ofLubrication revolutions may impact disintegration and, ultimately, dissolution of the tablets. The risk is high. Degradation Acetriptan is only susceptible to degradation at a high products temperature (. 105 ‹C). Blending is unlikely to impact degradation products; therefore, the risk is low. www.drugregulations.org 118
  • 119. Process Step Drug Product Justification CQA Assay In extreme cases, tablet weight variability can lead to out of-specification assay results. The risk is medium. Content Compression process variables such as feed frame uniformity paddle speed and press speed can cause tablet weight variability which could cause tablets to fall out-of- specification for CU. The risk is high.Compression Dissolution Tablet hardness may be impacted if compression force is not adjusted to accommodate batch-to-batch variability in ribbon density. Over-lubrication of the blend by the feed frame paddle may also slow dissolution. The risk is high. Degradation Acetriptan is only susceptible to degradation at a high products temperature (. 105 ‹C). Compression is unlikely to impact degradation products; therefore, the risk is low. www.drugregulations.org 119
  • 120.  Further risk assessment is performed on each high risk process step to identify which process variables may potentially impact the intermediate CQAs. Evaluation of all possible process variables that could potentially impact the quality attributes of the output material of any given process step is not feasible; Therefore, some of the variables were set constant based on current understanding www.drugregulations.org 120
  • 121.  The initial risk assessment of the overall manufacturing process presented earlier identified the risk of the pre-roller compaction blending and lubrication step to impact tablet content uniformity as high. Subsequently, blend uniformity was identified as an intermediate CQA of the powder blend from the pre-roller compaction blending and lubrication step. Process variables that could potentially impact blend uniformity were identified and their associated risk is evaluated www.drugregulations.org 121
  • 122. Process parameters Material attributes• Blender type • Acetriptan PSD• Order of addition• Blender fill level • Acetriptan cohesiveness• Rotation speed (if variable) • Acetriptan flowability• Number of revolutions • Excipient PSD• intensifier bar (on / off) • Excipient flowability• Holding time • Excipient bulk density• Discharge method• Drum-to-hopper transfer • Excipient moisture content• Environment (temperature and RH) • Excipient lot-to-lot variability Pre-Roller Compaction Blending and Lubrication Manufacturing CQA of output process step • Blend uniformity • Blend assay • Blend bulk density • Blend flowability • Blend compressibility / compactability • Appearance • Dimensions www.drugregulations.org 122
  • 123.  Following table presents the initial risk assessment for the pre-roller compaction blending and lubrication step www.drugregulations.org 123
  • 124. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend UniformityInput material attributes Variables Risk Justification & initial strategy assessmentAcetriptan PSD High The pilot BE study indicated that a d90 . 30 ƒÊm is needed for bioequivalence. Based on several lots of acetriptan analyzed during preformulation, the drug substance meeting this d90 criterion has poor flowability (ffc < 3.50) which may impact BU. The risk is high.Acetriptan Medium The specific energy of acetriptan Lot #1-4 indicated thatcohesiveness acetriptan is moderately to highly cohesive which will make achieving BU more challenging. The risk is medium.Acetriptan Medium The ffc value of acetriptan Lot #1-4 suggested poor flowflowability which could impact BU. The risk is medium.Excipient Low Filler comprises the majority (~ 80%) of the formulation.flowability MCC grade B02 and lactose monohydrate grade A01 are used in a 1:1 ratio because this ratio demonstrated good flowability (ffc . 7). Glidant and lubricant are used in small quantities and are unlikely to impact BU. The risk is low. www.drugregulations.org 124
  • 125. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend UniformityInput materials attributes Variables Risk Justification & initial strategy assessmentExcipient PSD Low Experience with previously approved ANDA 123456 and ANDA 456123 demonstrated that when the selected grades of MCC and lactose monohydrate are used in a 1:1 ratio, the flowability is good. This suggests that the PSD of the fillers will not impact BU. Because the quantities of glidant and lubricant used are small, their PSD are unlikely to impact BU. The risk is low.Excipient bulk density Low The 1:1 ratio of MCC to lactose monohydrate has a comparable bulk density to acetriptan. Glidant and lubricant are used in small quantities and their bulk densities are unlikely to impact BU. The risk is low.Excipient moisture Low The moisture content of the excipients is controlled percontent compendial/in-house specifications. Based on previous experience with approved ANDA 123456, excipient moisture content did not exhibit any significant impact on BU. The risk is lowExcipient lot-to-lot Large variations in the PSD of the excipients could impact BU;variability however, previous experience with the chosen excipient grades has shown that the lot-to-lot variability within grade is minimal. The risk is low. www.drugregulations.org 125
  • 126. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend UniformityBlending Variables Variables Risk Justification & initial strategy assessmentBlender Type Low Different blender types have different mixing dynamics. V-blender is selected based on equipment availability. The risk is low. However, if the blender type is changed during scale-up or commercialization, the risk should be re-evaluated.Order of addition Low Order of addition may impact the ease of evenly dispersing ingredients charged in lower quantities. Materials are added in the following order: lactose monohydrate, CCS, acetriptan, talc, and MCC. The risk is low.Rotation speed Medium Rotation speed is often fixed by equipment constraint.( rpm) Different size blenders have different rotation speeds. The rotation speed for the 16 qt blender is fixed at 20 rpm. The risk is medium. www.drugregulations.org 126
  • 127. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend UniformityBlending Variables Variables Risk Justification & initial strategy assessmentNumber of High Under- or over-blending will result in suboptimal BU. Therevolutions risk is highIntensifier bar Low The intensifier bar is often not needed to improve BU. In(on/off) addition, the intensifier bar may interfere with BU measurements if an NIR probe is used. The intensifier bar is fixed in the off position. The risk is low.Blender fill level High The blender fill level depends on equipment capacity, blend bulk density (0.43-0.48 g/cc) and batch size. Since the blender fill level may affect mixing dynamics, the risk is high. www.drugregulations.org 127
  • 128. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend UniformityBlending Variables Variables Risk Justification & initial strategy assessmentHolding time Medium Even if adequate BU is achieved, the drug substance may segregate prior to granulation during holding, dischargeBlender discharge Medium or transfer. The risk is medium.Drum-to-hopper MediumtransferEnvironment Low If not controlled, fluctuations in the facility temperature(temperature and and RH could impact BU. Routine environmentRH) temperature and RH set point in the cGMP manufacturing facility is fixed at 25 ºC ± 5% and 40%-60% RH, respectively, and will be monitored during manufacturing. The risk is low. www.drugregulations.org 128
  • 129.  A two-factor, three-level full factorial DOE, was used to investigate the impact of acetriptan PSD (d90) and number of revolutions (Nrev) on blend uniformity. Blender fill level is also likely to impact blend uniformity based on the initial risk assessment. Blender fill level was evaluated subsequent to the DOE. www.drugregulations.org 129
  • 130.  In order to ensure a homogeneous blend for any input acetriptan drug substance d90 within the range of 10-30 µm, an in-line NIR spectrophotometric method was developed and validated. This technology allows a real-time response and can be used at the laboratory, pilot and commercial scale. 13 www.drugregulations.org 0
  • 131.  Following table presents the risk reduction for the pre-roller compaction blending and lubrication process as a result of the development studies. Only the process variables that were initially identified as high risk to the blend uniformity are shown. 13 www.drugregulations.org 1
  • 132. Process Step: Pre-Roller Compaction Blending and LubricationOutput Material CQA: Blend Uniformity Variables Risk Justification & initial strategy assessmentAcetriptan PSD Low In order for the blending process to be robust enough to accommodate different acetriptan PSD, an in-line NIRNumber of Low method was developed for blending endpointrevolutions determination. Blender fill levels from 35-75% had noBlender fill level Low impact on blending endpoint. The risk was reduced from high to low. www.drugregulations.org 132
  • 133.  Based on the initial risk assessment of the overall manufacturing process: The risk of the roller compaction step to impact tablet content uniformity and dissolution was identified as high and The risk of the milling step to impact tablet content uniformity was identified as high. 13 www.drugregulations.org 3
  • 134. Process parameters Material attributes• Blend holding time prior to RC • Blend assay• Roller compactor type• Feed screw speed • Blend uniformity• Deaeration • Blend bulk density• Roller surface design • Blend flowability• Roller pressure • Blend compressibility /• Roller speed• Roller gap compactability• Environment (temperature and RH) • Compression Roller Compaction Manufacturing CQA of output process step • Ribbon thickness • Ribbon density www.drugregulations.org 134
  • 135. Process parameters Material attributes• Mill type• Blade configuration / type / orientation• Oscillation degree / speed • Ribbon thickness• Screen type • Ribbon density• Screen size• Number of recycles• Environment (temperature and RH) Milling Manufacturing CQA of output process step • Granule uniformity • Granule size distribution • Granule flowability • Granule bulk density • Assay of granule sieve cut www.drugregulations.org 135
  • 136.  Intermediate CQAs of the output material from the roller compaction and integrated milling step identified were: ◦ Ribbon density, ◦ Granule size distribution, ◦ Granule uniformity and ◦ Granule flowability www.drugregulations.org 136
  • 137.  Ribbon density is an intermediate CQA because it has a direct impact on granule particle size distribution, granule bulk and tapped density, granule flowability, and, ultimately, tablet hardness and dissolution. Granule size distribution, granule uniformity and granule flowability are intermediate CQAs because they are intimately related to tablet weight variability and content uniformity. The input material attributes and process parameters for this step that could potentially impact the four intermediate CQAs of the output material were identified and their associated risk was evaluated. www.drugregulations.org 137
  • 138. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentInput Material Attributes Ribbon Density Low The formulation has been optimized Granule Size Low (Section P.2.2). Consistent blend bulk Distribution density between 0.43-0.48 g/cc wasBlend bulk observed. This low variability of blend Granule Uniformity Lowdensity bulk density has a negligible impact on the four CQAs. The risk is low. Granule Flowability Low Ribbon Density Low The assay of the final blend was Granule Size Low consistently within 95.0-105.0% w/w Distribution (ranging from 98.7-101.2%). The risk isBlend assay low. Granule Uniformity Low Granule Flowability Low www.drugregulations.org 138
  • 139. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentInput Material Attributes Ribbon Density Low In-line NIR monitoring is used to Granule Size Low achieve adequate blend uniformity (RSDBlend Distribution < 5%). The risk is low.uniformity Granule Uniformity Low Granule Flowability Low Ribbon Density Low Compressibility and compactability Granule Size Low were optimized during formulationBlend Distribution development. The tablet demonstratedcompressibility/ good friability (< 0.2% weight loss) at Granule Uniformity Lowcompactability low hardness (5.0 kP) and achieved the desired dissolution at high hardness Granule Flowability Low (12.0 kP). The risk is low. www.drugregulations.org 139
  • 140. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentInput Material Attributes Ribbon Density Low The blend demonstrated acceptable Granule Size Low flowability (ffc > 6). The risk is low. DistributionBlend Granule Uniformity Lowflowability Granule Flowability Low www.drugregulations.org 140
  • 141. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density Low Due to the cohesiveness of acetriptan, no demixing was observed with extended Granule Size Low blending up to 500 revolutions. The risk of thePre-RC blend Distribution pre-RC blend to segregate during holding isholding time low. Granule Uniformity Low Granule Flowability Low Ribbon Density Low Due to operating principle differences between roller compactors, the ribbon attributes and Granule Size Low PSD of milled granules can vary significantly.Roller Distribution Based on availability, Alexanderwerk WP 120 iscompactor type selected and fixed for development work. The Granule Uniformity Low risk is low. However, if the roller compactor type is Granule Flowability Low changed during scale-up or commercialization, the risk should be re- evaluated. www.drugregulations.org 141
  • 142. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density Low Deaeration is used to enhance the flow of the blend feeding into the roller compactor. It will Granule Size Low always be used and is considered a fixedDeaeration Distribution factor. The risk is low Granule Uniformity Low Granule Flowability Low Ribbon Density Low Feed screw speed is a floating parameter dependent on roller pressure and roller gap. Granule Size Medium The risk is medium.Feed screw Distributionspeed Granule Uniformity Medium Granule Flowability Low www.drugregulations.org 142
  • 143. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process VariablesRoller surface Ribbon Density Low Roller surface design may impact the powerdesign feeding from the slip region into the nip Granule Size Low region. For this product, a roller with a Distribution knurled surface was selected to enhance Granule Uniformity Low material feeding by providing more friction than a smooth surface roller and is considered Granule Flowability Low a fixed factor. The risk is lowRoller pressure Ribbon Density High Ribbon density is directly related to roller pressure and, in turn, may impact the PSD, Granule Size High flowability, uniformity, compressibility and Distribution compactability of the milled granules. The risk Granule Uniformity High is high. Granule Flowability High www.drugregulations.org 143
  • 144. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density Medium The roller speed determines the throughput of the process and is adjusted according to the Granule Size Medium selected feed screw speed to avoid material Distribution build-up. In addition, roller speed is inverselyRoller speed related to the dwell time for particle Granule Uniformity Medium compaction which may impact the ribbon Granule Flowability Medium density. Based on previous experience with approved ANDA 123456 using roller compaction, roller speed is fixed to 8 rpm. Adjustment may be needed. The risk is medium. Ribbon Density High According to the Johanson model¹¹, ribbon density is inversely related to the roller gap Granule Size High and, in turn, it may impact PSD, flowability,Roller gap Distribution uniformity, compressibility and compactability Granule Uniformity High of the milled granules. The risk is high. Granule Flowability High www.drugregulations.org 144
  • 145. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density NA The type of mill governs the type of attrition and impacts the PSD of the milled granules. Granule Size Low An integrated mill was selected and isMill type Distribution considered a fixed factor. The risk is low. Granule Uniformity Low However, if the mill type is changed during scale-up or commercialization, the risk should Granule Flowability Low be re-evaluated. Ribbon Density NA The mill screen type may impact the granule size distribution, granule uniformity and Granule Size Low granule flowability obtained from the millingMill screen type Distribution step. A mesh screen is selected based on Granule Uniformity Low availability. The risk is low. If the mill screen type is changed, risk will Granule Flowability Low need to be reassessed Johanson, J. R. A rolling theory for granular solids. ASME, Journal of Applied Mechanics Series E, 1965, 32(4): 842–848 www.drugregulations.org 145
  • 146. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density NA The ribbon is formed during the roller compaction step Granule Size High The mill speed may impact the PSD of theMill speed Distribution milled granules which can potentially impact granule uniformity and flowability. The risk is Granule Uniformity High high. Granule Flowability High Ribbon Density NA The ribbon is formed during the roller compaction step.Blade Granule Size Low The milling blade can apply variable shear toconfiguration Distribution the material based on design. Low shear can result in a coarser but more uniform PSD, Granule Uniformity Low whereas high shear can result in a non- Granule Flowability Low uniform, multi-modal PSD. The resulting PSD affects flowability and uniformity. The risk is low because the blade is fixed by equipment design. www.drugregulations.org 146
  • 147. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density NA The ribbon is formed during the roller compaction step.Mill screen Granule Size High The mill screen orifice size directlyorifice size Distribution impacts PSD which can potentially Granule Uniformity High impact granule uniformity and Granule Flowability High flowability. The risk is high. Ribbon Density Medium If excessive powder leakage occurs Granule Size Medium during roller compaction or excessiveNumber of Distribution fines are generated during milling,recycles Granule Uniformity Medium recycles of the fine particles may be considered. However, the number of Granule Flowability Medium recycles may impact the homogeneity of the granule quality attributes. The goal is to not recycle material. The risk is medium. www.drugregulations.org 147
  • 148. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification & initial strategy CQAs assessmentRoller Compaction and Milling Process Variables Ribbon Density NA If not controlled, fluctuations in the Granule Size High facility temperature and RH couldEnvironment Distribution impact the CQAs. Routine environment(temperature Granule Uniformity High temperature and RH set point in theand RH) cGMP manufacturing facility is fixed at Granule Flowability High 25 ºC ± 5% and 40%-60% RH, respectively, and will be monitored during manufacturing. The risk is low. www.drugregulations.org 148
  • 149.  The main objective of the study was to evaluate the effect of the roller compaction and integrated milling process parameters on the quality attributes of the ◦ ribbon, ◦ milled granules and ◦ finished drug product using DOE. The process parameters investigated were ◦ roller pressure, ◦ roller gap, ◦ milling speed and ◦ mill screen orifice size. www.drugregulations.org 149
  • 150.  A preliminary feasibility experiment was conducted. The effect of roller pressure on the quantity of by-pass material (un-compacted material) was studied. The study showed that within the roller pressure range of 20-80 bar, the quantity of by-pass material was less than 5% and the potency matched that of the blend fed into the roller compactor. Therefore, the roller pressure range of 20-80 bar was suitable for further studies. During the feasibility study, product temperature was monitored by a non-invasive measuring device. No significant increase (> 5°C) was observed. The ranges for roller gap, mill speed and mill screen orifice size were selected based on previous experience with approved ANDA 123456 and ANDA 456123. For this study, a 24-1 fractional factorial DOE was used and three center points were included to evaluate if any curvature effects exist www.drugregulations.org 150
  • 151.  Roller pressure had a significant impact on ribbon density, mean granule size (d50), granule flowability, tablet hardness and tablet content uniformity. Roller gap exhibited a significant impact on ribbon density, granule flowability, tablet hardness and tablet content uniformity. Mill screen orifice size had a significant impact on mean granule size (d50), granule flowability and tablet content uniformity. Mill speed did not show a significant impact on any of the responses studied. In addition, no curvature effects were observed for any of the responses. 15 www.drugregulations.org 1
  • 152.  Based on the results of the DOE study, ◦ roller pressure, ◦ roller gap and ◦ mill screen orifice size were identified as the CPPs while mill speed was determined to be not critical. Results of process development done by DOE were used to identify an appropriate range for each CPP that would ensure that the targets for all quality attributes are met concurrently. 15 www.drugregulations.org 2
  • 153. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification for the risks CQAs assessmentRoller Compaction and Milling Process VariablesRoller pressure Ribbon Density Low An acceptable range for roller pressure was identified during the DOE. Within the range Granule Size Low (20-77 bar), all CQAs met the predefined Distribution acceptance criteria by using an appropriate Granule Uniformity Low roller gap. Thus, the risk is reduced from high Granule Flowability Low to low.Roller gap Ribbon Density Low An acceptable range for roller gap was identified during the DOE. Within the range Granule Size Low (1.2-2.4 mm), all CQAs met the predefined Distribution acceptance criteria by using an appropriate Granule Uniformity Low roller pressure. Thus, the risk is reduced from high to low. Granule Flowability Low www.drugregulations.org 153
  • 154. Process Step: Roller compaction and integrated milling processOutput Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity andGranule Flowability Variables Output Material Risk Justification for the risks CQAs assessmentRoller Compaction and Milling Process VariablesMill screen Ribbon Density Low The mill screen orifice size (1.0 mm) wasorifice size selected because it allows a wider acceptable Granule Size Low operating range for both roller pressure and Distribution roller gap compared to the other studied sizes Granule Uniformity Low (0.6 mm and 1.4 mm). When using the selected mill screen orifice size (1.0 mm), all Granule Flowability Low CQAs met the predefined acceptance criteria. Thus, the risk is reduced from high to low. www.drugregulations.org 154
  • 155.  The initial risk assessment of the overall manufacturing process identified the risk of the final blending and lubrication step to impact tablet dissolution as high. The lubrication process variables that could potentially impact tablet dissolution were identified and their associated risk was evaluated. www.drugregulations.org 155
  • 156. Process parameters Material attributes• Blender type • Granule uniformity• Order of addition • Granule size distribution• Blender fill level • Granule flowability• Rotation speed (if variable)• Number of revolutions • Granule bulk density• Intensifier bar (on / off)Holding time • Assay of granule sieve cut• Discharge method • Magnesium stearate• Drum-to-hopper transfer • specific surface area• Environment (temperature and RH Final blending & lubrication Manufacturing CQA of output process step • Blend assay • Blend uniformity • Blend bulk density • Blend flowability • Blend compressibility / compactability www.drugregulations.org 156
  • 157.  Following table presents the initial risk assessment of the final blending and lubrication step. www.drugregulations.org 157
  • 158. Process Step: Final Blending and LubricationOutput Material CQA: Tablet DissolutionInput material attributes Variables Risk Justification & initial strategy assessmentGranule uniformity Low The granules produced during roller compaction development demonstrated uniformity with % RSD < 3%. Therefore, granule uniformity should have little impact on tablet dissolution. The risk is low.Assay of granule Low Sieve cuts studied during roller compaction developmentsieve cut ranged in assay from 98.2% to 101.2%. This low variability will have little impact on tablet dissolution. The risk is low.Granule flowability Low For a ribbon relative density of 0.68 to 0.81, the flowability was good (ffc > 6) and should not impact tablet dissolution. The risk is low.Granule size Low The rapid disintegration of the tablets is achieved bydistribution using 5% CCS in the formulation. The variability in granule size distribution observed during roller compaction development showed no impact on dissolution. Therefore, the risk is low. www.drugregulations.org 158
  • 159. Process Step: Final Blending and LubricationOutput Material CQA: Tablet DissolutionInput material attributes Variables Risk Justification & initial strategy assessmentGranule bulk Low The granule bulk density is consistently between 0.62-density 0.69 g/cc. The low variability has little impact on tablet dissolution. The risk is low.Magnesium High The lubricating effect of magnesium stearate improves asStearate specific specific surface area increases. The risk of over-surface area lubrication leading to retarded disintegration and dissolution is high. www.drugregulations.org 159
  • 160. Process Step: Final Blending and LubricationOutput Material CQA: Tablet DissolutionLubrication process variables Variables Risk Justification & initial strategy assessmentBlender type Low Due to differences in the operating principle, different types of blenders may impact blending efficiency. Based on availability, V-blender is selected. The risk is low. However, if the blender type is changed during scale-up or commercialization, the risk should be re-evaluated.Order of addition Low Granules and talc are blended together first, followed by magnesium stearate. Magnesium stearate is traditionally charged last to lubricate the other particles. Order of addition is fixed and has a minimal impact on dissolution. The risk is low.Rotation speed Medium Rotation speed is often fixed by equipment constraint.(rpm) Different size blenders have different rotation speeds. The rotation speed for the 16 qt blender is fixed at 20 rpm. The risk to impact tablet dissolution is medium.Number of High Over-lubricating may result in retarded disintegrationrevolutions and dissolution. For a BCS class II compound like acetriptan, the risk is high. www.drugregulations.org 160
  • 161. Process Step: Final Blending and LubricationOutput Material CQA: Tablet DissolutionLubrication process variables Variables Risk Justification & initial strategy assessmentIntensifier bar Low If the intensifier bar is on, then it may cause granule(on/off) attrition. To avoid generating fines, the intensifier bar is fixed in the off position during the final blending and lubrication. The risk is lowBlender fill level Medium Blender fill level may affect mixing dynamics. It is fixed for these development studies but could change upon scale-up. The risk is medium.Holding time Low These three process variables are not related to dissolution. The risk is low.Blender discharge LowDrum-to-hopper LowtransferEnvironment Low If not controlled, fluctuations in the facility temperature(temperature and and RH could impact the CQAs. Routine environmentRH) temperature and RH set point in the cGMP manufacturing facility is fixed at 25 ºC ± 5% and 40%-60% RH, respectively, and will be monitored during manufacturing. The risk is low. www.drugregulations.org 161
  • 162.  A study was performed to investigate the effect of magnesium stearate specific surface area and number of revolutions during lubrication on tablet hardness, disintegration, and dissolution. Within the ranges studied, magnesium stearate specific surface area (5.8-10.4 m2/g) and number of revolutions (60-100) did not have a significant impact on the drug product quality attributes studied 16 www.drugregulations.org 2
  • 163. Process Step: Final Blending and LubricationOutput Material CQA: Tablet DissolutionLubrication process variables Variables Risk Justification & initial strategy assessmentMagnesium Low Within the range 5.8-10.4 m2/g, magnesium stearatestearate specific specific surface area does not adversely impact tabletsurface area dissolution. The risk is reduced from high to low and this material attribute will be controlled in the control strategyNumber of Low A proven acceptable range for number of revolutionsrevolutions (60-100) was established for this scale based on elegant tablet appearance and rapid dissolution. The risk is reduced from high to low and number of revolutions is controlled in the control strategy www.drugregulations.org 163
  • 164.  Based on the initial risk assessment of the overall manufacturing process shown earlier, the risk of the compression step to impact ◦ content uniformity and ◦ dissolution of the tablets was identified as high. Process variables that could potentially impact these two drug product CQAs were identified and their associated risk was evaluated. The results of the initial risk assessment of the compression process variables are summarized in following tables. www.drugregulations.org 164
  • 165. Process parameters Material attributes• Press type and number of stations• Tooling design • Blend assay• Feed frame paddle speed • Blend uniformity• Feeder fill depth • Granule size distribution• Pre-compression force• Main compression force • Blend bulk density• Press speed (dwell time) • Blend flowability• Hopper design • Blend compressibility /• Hopper fill level compactability• Drop height of finished tablets• Run time• Environment (temperature and RH) Compression (Tableting) Manufacturing CQA of output process step • Appearance • Dimensions (length, width, thickness) • Weight (individual and composite) • Hardness • Friability • Content uniformity • Assay • Disintegration www.drugregulations.org • Dissolution 165
  • 166. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionInput material attributesVariables Drug Risk Justification & initial strategy Product assessment CQA’sBlend Content Low The blend assay varied between 98.3% and 101.7%Assay Uniformity during the lubrication process development. This low variability is unlikely to impact CU and Dissolution Low dissolution. The risk is low.Blend Content Low The lubricated blend demonstrated acceptable BUuniformity Uniformity (% RSD < 3%) during the lubrication process development. Therefore, the risk is low Dissolution LowGranule Content Low The granule size distribution is controlled bysize Uniformity milling after the roller compaction process step.distribution The granules demonstrated good flowability (ffc > 6) and should not impact CU. The risk is low. Dissolution Low The formulation contains 5% CCS and the variability in granule size distribution observed during roller compaction development showed no impact on dissolution. The risk is low. www.drugregulations.org 166
  • 167. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionInput material attributes Variables Drug Product Risk Justification & initial strategy CQA’s assessmentBlend Content Low Blend flowability could impact powder flow from theflowability Uniformity hopper to the feed frame and, ultimately, to the die cavity. However, adequate flow was demonstrated during roller Dissolution Low compaction development. Small amounts of extragranular glidant and lubricant will not impact blend flowability. The risk is low.Blend Content Low CU is unaffected by the blend compressibility andcompressibi Uniformity compactability. The risk is low.lity and Dissolution Low Suboptimal blend compressibility and compactability cancompactabil affect tablet hardness. The compressibility andity compactability of the blend are directly related to the ribbon relative density achieved during roller compaction. Ribbon relative density may vary from batch-to-batch and may cause tablet hardness variation if the compression force is not adjusted. This may, in turn, impact dissolution. The risk is highBlend bulk Content Low The blend bulk density is consistently between 0.62-0.69density Uniformity g/cc. The low variability has little impact on CU and dissolution. The risk is low. Dissolution Low www.drugregulations.org 167
  • 168. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionCompression Process Variables Variables Drug Product Risk Justification & initial strategy CQA’s assessmentPress type Content Low The press type was selected based on equipmentand number Uniformity availability and 3 stations will be used duringof stations development. The same press model but all 51 stations Dissolution Lowused will be used for both exhibit and commercial scale. Thus, the risk is low.Tooling Content Low Tooling design was selected to compress a tablet with adesign Uniformity similar size and shape as the RLD. No picking was observed during the final blending and lubrication studies. Dissolution Low The risk is lowFeed frame Content High A greater than optimal feed frame paddle speed may causepaddle Uniformity over-lubrication. A lower than optimal feed frame paddlespeed speed may cause inconsistent die filling. The risk is high. Dissolution High www.drugregulations.org 168
  • 169. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionCompression Process Variables Variables Drug Risk Justification & initial strategy Product assessment CQA’sFeeder fill Content Low The feeder fill depth is set to 80% full and is monitoreddepth Uniformity and controlled by an automatic feedback control loop on the tablet press. The risk is low. Dissolution LowPre- Content Low CU is dominated by BU and flowability and is unrelated tocompression Uniformity pre-compression force. The risk is lowforce Dissolution Medium A greater than optimal pre-compression force may cause lamination. A lower than optimal pre-compression force may trap air in the tablets, leading to capping. Either scenario could impact dissolution. The pre-compression force is set to 1.0 kN based on experience with similar formulations compressed on the same equipment. Adjustment may be needed. The risk is medium.Main Content Low CU is dominated by BU and flowability and is unrelated tocompression Uniformity main compression force. The risk is low.force Dissolution High Suboptimal compression force may affect tablet hardness and friability and, ultimately, dissolution. The risk is high. www.drugregulations.org 169
  • 170. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionCompression Process Variables Variables Drug Risk Justification & initial strategy Product assessment CQA’sPress speed Content High A faster than optimal press speed may cause inconsistent(dwell time) Uniformity die filling and weight variability which may then impact CU and dissolution. For efficiency, the press speed will be set Dissolution High as fast as practically possible without adversely impacting tablet quality. The risk is high.Hopper Content Low Since acetriptan is roller compacted with excipients, thedesign and Uniformity risk of drug substance segregation is minimized. Tabletvibration press vibrations and the hopper angle design are unlikely Dissolution Low to have an impact on CU and dissolution. The risk is low.Hopper fill Content Low The blend has acceptable flowability and the hopper filllevel Uniformity level is maintained at 50%. Maintaining the hopper fill level makes it improbable that this parameter will impact CU Dissolution Low and dissolution. The risk is low. www.drugregulations.org 170
  • 171. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionCompression Process Variables Variables Drug Risk Justification & initial strategy Product assessment CQA’sDrop height Content Medium Finished tablets may chip, crack, cleave or break if theof finished Uniformity drop height is great. The risk is medium.tablets Dissolution MediumCompression Content Medium It is possible during long compression run times that therun time Uniformity CU may drift. The risk is medium. Dissolution Low It is unlikely for compression run time to cause a drift that leads to a dissolution failure. The risk is low.Environment Content Low If not controlled, fluctuations in the facility temperature(temperature Uniformity and RH could impact the CQAs. Routine environmentand RH) temperature and RH set point in the cGMP manufacturing Dissolution Low facility is fixed at 25 ºC ± 5% and 40%-60% RH, respectively, and will be monitored during manufacturing. The risk is low. www.drugregulations.org 171
  • 172.  A screening study was conducted to investigate the impact of the feeder frame paddle speed (8-20 rpm) on tablet quality. Since the final blend flows well, changes in feeder frame paddle speed within the specified range had no impact on tablet weight variability or content uniformity. Tablet dissolution was also unaffected by changes in feeder speed, suggesting that over-lubrication due to the additional mixing is not a concern. This process variable was eliminated from further study.. www.drugregulations.org 172
  • 173.  Compression force and press speed (which is related to dwell time) can affect numerous quality attributes including ◦ hardness, ◦ disintegration, ◦ dissolution, ◦ assay, ◦ content uniformity, ◦ friability, ◦ weight variability and ◦ appearance. www.drugregulations.org 173
  • 174.  The density of the ribbon following roller compaction may also impact the compressibility and compactability of the granules which would then impact tablet hardness and dissolution. Therefore, a 2³ full factorial DOE with three center points was performed to understand the effects of these parameters on tablet quality attributes. Pre-compression force is important to reduce entrapped air that can impact the tablet integrity. However, based on previous experience with similar formulations compressed with similar tooling (ANDA 123456), the pre- compression force was fixed to 1 kN for this DOE. www.drugregulations.org 174
  • 175.  Summary of Tablet Compression Process Development Within the range studied (8-20 rpm), feeder frame paddle speed did not impact the tablet dissolution. A press speed in the range of 20-60 rpm did not show any significant impact on the responses investigated. An acceptable range for compression force was identified. Force adjustments can be made to accommodate the acceptable variation in ribbon relative density (0.68- 0.81) between batches. 17 www.drugregulations.org 5
  • 176. Process Step: Tablet CompressionOutput Material CQA: Content Uniformity, DissolutionCompression Process Variables Variables Drug Risk Justification & initial strategy Product assessment CQA’sBlend Dissolution Low Compression force can be adjusted to accommodate thecompressibility acceptable ribbon relative density (0.68-0.81) in order toand achieve the target tablet hardness. The risk is reducedcompactability from high to low.Feeder frame Content Low Feeder frame paddle speed in the range of 8-20 rpm hadpaddle speed Uniformity no impact on CU or dissolution. The same tablet press model will be used for pilot scale and commercial scale Dissolution Low manufacture. If necessary, slight adjustments in the feeder frame paddle speed may be made when all stations are utilized. The risk is reduced from high to low.Main Dissolution Low Tablet hardness increases with compression force. Withincompression the compression force range studied, the resulting tabletforce hardness did not adversely affect dissolution and > 90% dissolution at 30 min was achieved. The risk is reduced from high to low.Press speed Content Low A press speed of 20-60 rpm had no impact on CU or(dwell time) Uniformity dissolution. Thus, the risk is reduced from high to low. Dissolution Low www.drugregulations.org 176
  • 177. Role of Quality Risk Management in Development & Manufacturing Product Process Process Scale-up Manufacturing Development Development & Tech TransferProduct/prior Process Process Knowledge Understanding History Risk Risk Risk RiskAssessment Assessment Control Review Excipient & Process Product quality Continual drug substance design space control strategy improvement design space Quality Risk Management
  • 178. 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 17 www.drugregulations.org 8