Quality by Design : Quality Target Product Profile & Critical Quality Attributes

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

This presentation - Part II in the series- deals with the concepts of Quality Target Product Profile and Critical Quality attributes.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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Quality by Design : Quality Target Product Profile & Critical Quality Attributes

  1. 1. Quality Target Product Profile (QTPP ) And Critical Quality Attributes Presentation prepared by Drug Regulations – a not for profit organization. Visit www.drugregulations.org for the latest in Pharmaceuticals. www.drugragulations.org 1
  2. 2. Product Profile  Quality Target Product Profile (QTPP) CQA’s  Determine “potential” critical quality attributes (CQAs)Risk Assessments  Link raw material attributes and process parameters to CQAs and perform risk assessment Design Space  Develop a design space (optional and not required)Control Strategy  Design and implement a control strategy Continual  Manage product lifecycle, including continual Improvement improvement www.drugragulations.org 2
  3. 3. Product Profile CQA’s  This presentation Part III of theRisk Assessments series “QbD for Beginners” covers basic aspects of Design Space ◦ Quality Target Product Profile (QTPP) andControl Strategy ◦ Critical Quality attributes. Continual Improvement www.drugragulations.org 3
  4. 4. Dissolution ? Dose ? Appearance ?ContentUniformity ? Hardness ? www.drugragulations.org 4
  5. 5.  The QTPP is an essential element of a QbD approach and forms the basis of design for the development of the product It describes the design criteria for the product, and should therefore form the basis for development of the ◦ CQAs, ◦ CPPs, and ◦ Control strategy The QTPP provides an understanding of what will ensure the quality, safety, and efficacy of a specific product for the patient and is a starting point for identifying the CQAs. www.drugragulations.org 5
  6. 6. A prospective summary ofthe quality characteristics ofa drug product that ideallywill be achieved to ensure thedesired quality, taking intoaccount safety and efficacy ofthe drug product : ICH Q8(R2) www.drugragulations.org 6
  7. 7. By beginning with the end inmind, the result of development is a robust formulation andmanufacturing process with anacceptable control strategy thatensures the performance of the drug product www.drugragulations.org 7
  8. 8.  Considerations for the quality target product profile could include: ◦ Intended use in clinical setting, route of administration, dosage form, delivery systems; ◦ Dosage strength(s); ◦ Container closure system; ◦ Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance)appropriate to the drug product dosage form being developed; ◦ Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product. www.drugragulations.org 8
  9. 9.  For ANDAs, the target should be defined early in development based on ◦ The properties of the drug substance (DS), ◦ Characterization of the RLD product and ◦ Consideration of the RLD label and ◦ Intended patient population www.drugragulations.org 9
  10. 10.  The TPQP should only include patient relevant product performance. For example, if particle size is critical to the dissolution of a solid oral product, then the TPQP should include dissolution but not particle size. Particle size would be a critical material attribute and thus included in the process description and control strategy. www.drugragulations.org 10
  11. 11.  All product attributes to ensure equivalency of safety and efficacy with respect to RLD. QTPP may change as more is available. Development report to contain evolution of QTPP End result is not final QTPP but An acceptable control strategy and regulatory specification. For example, the final impurity and residual solvent specifications may depend on the properties of excipients used in the formulation. www.drugragulations.org 11
  12. 12. Example from IWG Case Study: Sakura case study Quality Target Product Profile (QTPP) Safety and Efficacy RequirementsICH-GCG ASEAN, Kuala Lumpur, 26-28 July 2010 10 www.drugragulations.org
  13. 13. Quality Target Product Profile (QTPP) Safety and Efficacy Requirements Translation into Characteristics / Tablet Quality Target Product Requirements Profile (QTPP)Dose 30 mg Identity, Assay and Uniformity Appearance, elegance, size, No off-taste, uniform color,Subjective Properties unit integrity and other and suitable for global market characteristics Acceptable hydrolysis degradate Impurities and/or degradates levels at release, appropriatePatient Safety – chemical purity below ICH or to be qualified manufacturing environment controls PSD that does not impactPatient efficacy – Acceptable API PSD bioperformance or pharm Particle Size Distribution (PSD) Dissolution processing Degradates below ICH or to beChemical and Drug Product Hydrolysis degradation & qualified and no changes in Stability: 2 year shelf life dissolution changes bioperformance over expiry (worldwide = 30ºC) controlled by packaging period ICH-GCG ASEAN, Kuala Lumpur, 26-28 July 2010 www.drugragulations.org 11
  14. 14. www.drugragulations.org 14
  15. 15. Quality Attribute Target CriticalityDosage form Tablet, maximum weight 200mg Not ApplicablePotency 20 mg Not applicablePharmacokinetics Immediate release enabling Related to dissolution Tmax in 2 hours or lessAppearance Tablet conforming to Critical description shape and sizeIdentity Positive for acetriptan CriticalAssay 95 – 105% CriticalImpurities ACE12345 NMT 0.5%,other Critical impurities NMT 0.2%, total NMT 1%Water NMT 1% Not critical – API not sensitive to hydrolysisContent Uniformity Meets USP CriticalResistance to 5-12kP Not critical since related toCrushing (Hardness) dissolution www.drugragulations.org 15
  16. 16. Quality Attribute Target CriticalityFriability NMT 1.0% Not criticalDissolution Consistent with immediate release, Critical e.g., NLT 75% at 30minsDisintegration NMT 15mins CriticalMicrobiology If testing required, meets USP Critical only if drug product criteria supports microbial growth www.drugragulations.org 16
  17. 17. www.drugragulations.org 17
  18. 18.  RLD : MR Tablets, 10 mg, IR & ER component , BCS class I NDA : 2009 in NDA “aaaaaa” Indications: Therapeutic relief, active ingredient Z that acts through the CNS. Tablet MR was developed based on corresponding IR 3 mg formulation , approved in 2005 in NDA “bbbbbb” ; and ANDA approval for Example IR Tablets was (ANDA aaaaaa) was in 2010. Dosage: Once-a-day dosing ◦ Immediate onset of therapeutic relief similar to the IR product ◦ Maintenance of the therapeutic effect. ◦ 10 mg once daily in adults & a maximum daily dose of 20 mg. ◦ The tablet is scored to allow for 5 mg dosing,  Elderly patients or  Patients with hepatic insufficiency who do not clear the drug as rapidly as normal www.drugragulations.org 18
  19. 19.  The label warns of the potential risk of dose dumping that may occur with the co-ingestion of alcohol. IR phase achieves plasma concentrations comparable to the IR product (3 mg) through the first two hours for rapid onset of the therapeutic effect. The ER phase sustains plasma concentrations of the drug through 24 hours for maintenance of the therapeutic effect. The product label indicates that the drug can be taken regardless of meals because there is no food effect. www.drugragulations.org 19
  20. 20. QTPP Element Target JustificationDosage Form MR Tablet Pharmaceutical equivalence requirement: Same dosage formRoute of Administration Oral Pharmaceutical equivalence requirement: Same route of administrationDosage Strength 10 mg Pharmaceutical equivalence requirement: Same strengthPharmacokinetics Fasting Study and Bioequivalence requirement Fed Study 90 % confidence Initial plasma concentration through interval of the PK the first two hours that provides a parameters, AUC0- clinically significant therapeutic 2, AUC2-24, effect followed by a sustained plasma AUC0-∞ and concentration that maintains the Cmax, should fall therapeutic effect within bioequivalence limits www.drugragulations.org 20
  21. 21. QTPP Element Target JustificationStability At least 24-month Equivalent to or better than RLD shelf-life at room shelf-life temperature Physical attributes Identification Assay Pharmaceutical equivalence Content Uniformity requirement: Meeting the sameDrug product quality compendial or other applicableattributes Degradation products (quality) standards (i.e., identity, Residual solvents assay, purity, and quality) Drug release Microbial Limits Water Content www.drugragulations.org 21
  22. 22. QTPP Element Target JustificationContainer Closure System Suitable container HDPE bottles with Child Resistant closure system to (CR) Caps are selected based on achieve the target similarity to the RLD packaging. No shelf-life and to further special protection is needed ensure tablet due to the stability of drug substance integrity during Z. shippingAdministration/concurrence A scored tabletwith labeling can be divided into two 5 mg tablets. Information is provided in the RLD labeling The tablet can be taken without regard to food (no food effect).Alternative methods of Noneadministration None are listed in the RLD labeling. www.drugragulations.org 22
  23. 23. FDA Example : QbD IR TabletQuality Target Product Profile (QTPP) www.drugragulations.org 23
  24. 24.  RLD : Acetriptan Tablets 20mg , BCS class II , IR uncoated Tablets NDA : NDA 211168 approved in 2000 Indications: Therapeutic relief of moderate to severe symptoms. Dosage: One tablet twice a day ◦ Maximum daily dose of 40 mg. ◦ May be swallowed whole with a glass of water with or without food. Well absorbed after oral administration. ◦ Tmax is 2.5 hours in patients. ◦ The mean absolute bioavailability is approximately 40%. ◦ The AUC and Cmax of are increased by approximately 8% to 12% following oral dosing with a high fat meal. ◦ The terminal elimination half-life is approximately 4 hours. www.drugragulations.org 24
  25. 25. QTPP Element Target JustificationDosage Form IR Tablets Pharmaceutical equivalence requirement: Same dosage formDosage Design Immediate release Immediate release design needed to tablet without a meet label claims score or coatingRoute of Administration Oral Pharmaceutical equivalence requirement: Same route of administrationDosage Strength 20 mg Pharmaceutical equivalence requirement: Same strengthPharmacokinetics Immediate release Bioequivalence requirement enabling Tmax in 2.5 hours or less; Needed to ensure rapid onset and Bioequivalent to efficacy RLD www.drugragulations.org 25
  26. 26. QTPP Element Target JustificationStability At least 24-month Equivalent to or better than RLD shelf-life at room shelf-life temperature Physical attributes Identification Assay Pharmaceutical equivalence requirement: Must meet the sameDrug product quality Content Uniformity compendial or other applicableattributes (quality) standards (i.e., identity, Dissolution assay, purity, and quality). Degradation products Residual solvents Water Content Microbial Limits www.drugragulations.org 26
  27. 27. QTPP Element Target JustificationContainer Closure System Container closure Needed to achieve the target shelf- system qualified life and to ensure tablet integrity as suitable for this during shipping. drug product.Administration/concurrence Similar food effect RLD labeling indicates that a high fatwith labeling as RLD meal increases the AUC and Cmax by 8-12%. The product can be taken without regard to food.Alternative methods of None None are listed in the RLD labeling.administration www.drugragulations.org 27
  28. 28. Identity POTENTIAL QUALITY ATTRIBUTES Criticality assessment Safety & Efficacy • Appearance Potency • Assay CQTPP • Crystallinity • CU Q • Degradation A • Disintegration s • Dissolution Purity • IR / MR • Microbiology • Sterility Others www.drugragulations.org 28
  29. 29.  A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. ICH Q 8 R2. From the perspective of product development, the FDA Office of Generic Drugs further defines CQAs of drug products as those that have the highest potential to be altered by formulation or process variables. Therefore, these attributes should be investigated in product and process development in order to define an appropriate control strategy. CQAs are generally associated with the ◦ Drug substance, ◦ Excipients, ◦ Intermediates (in-process materials) and ◦ Drug product. www.drugragulations.org 29
  30. 30.  CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability. CQAs for other delivery systems can additionally include more product specific aspects, such as ◦ aerodynamic properties for inhaled products, ◦ sterility for parenterals, and ◦ adhesion properties for transdermal patches. For drug substances, raw materials and intermediates, the CQAs can additionally ◦ include those properties (e.g., particle size distribution, bulk density) that affect drug product CQAs. www.drugragulations.org 30
  31. 31.  Drug product CQAs derived from the ◦ Quality target product profile and/or ◦ Prior knowledge The CQA’s are used to guide the product and process development. The list of potential CQAs can be modified when the formulation and manufacturing process are selected and as product knowledge and process understanding increase. Quality risk management can be used to prioritize the list of potential CQAs for subsequent evaluation. Relevant CQAs can be identified by an iterative process of quality risk management and experimentation that assesses the extent to which their variation can have an impact on the quality of the drug product. www.drugragulations.org 31
  32. 32.  All quality attributes are target elements of the drug product and should be achieved through ◦ a good quality management system, ◦ appropriate formulation/process design and development. From the perspective of pharmaceutical development, the subset of CQAs of the drug product that also have a high potential to be impacted by the formulation or process variables are investigated. Investigation culminates in an appropriate control strategy. www.drugragulations.org 32
  33. 33.  Accurate measurement of product attributes depends on the capability analytical methodology. Analytical method should be assessed to determine the degree of variability. Variability due to analytical method itself versus the degree of variability inherent to the product. Use ANOVA-based statistical methods Quantitative discernment between different sources of variability including, ◦ Instrument, ◦ Operator and ◦ Sample. Important for study of Product attributes as a function of formulation and process parameters in a design of experiments (DOE). www.drugragulations.org 33
  34. 34.  Severity of harm (safety and efficacy) before taking into account risk control; The rationale for distinguishing CQAs from other quality attributes; Link to the patient as described in the QTPP; Basis on which the CQAs have been developed (e.g., prior knowledge, scientific first principles, and experimentation); and Inter-dependencies of the different CQAs. www.drugragulations.org 34
  35. 35. • When the quality attribute has an impact on the patient. CQA High Risk• Efficacy: What if the patient receives the wrong dose?• Safety: What if the product contains potentially harmful CQA/ degradants? QA QA• Quality: What if the product is damaged – will the patient take it?• Continuum of criticality – Low Risk QA cascade from “critical” to “not critical www.drugragulations.org 35
  36. 36. Continual Improvement iteration Potential Impact toQTPP Safety Non - Critical Efficacy & Quality? Low Risk Severity@ Critical @ A Severity Scale is used to assess relative magnitude of impact. A change in criticality only occurs w/ a change in severity. High risk www.drugragulations.org 36
  37. 37.  Pharmaceutical development studies Technology transfer Manufacturing experience e.g. Internal and Vendor audits Raw material testing data Change management activities Stability reports Product Quality Reviews/Annual Product Reviews Complaint Reports; Adverse event reports; Recalls Trend data; Technical investigations Suppliers and Contractors Product history and /or manufacturing history www.drugragulations.org 37
  38. 38. FDA Example :QbD MR Tablet www.drugragulations.org 38
  39. 39. Quality Attributes of the Target Is it a Justification Drug Product CQA? Color and shape No Color, shape and appearance are not directly acceptable to the linked to safety and efficacy. Therefore, they are not critical. . The target is set to ensure Appearance patient. No visual patient acceptability tablet defects observed. Odor No unpleasant odor No In general, a noticeable odor is not directly linked to safety and efficacy, but odor can affect patient acceptability and lead to complaints. For this product, neither the drug substance nor the excipients have an unpleasant odor. No organic solvents will be used in the drug product manufacturing processPhysicalAttributes Size Similar to RLD Yes Tablet size correlates to swallowability; therefore, it is critical. For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet size and volume is set similar to the RLD. Score and Scored and can be Yes The RLD tablet is scored and labeled for half- Splitability split for half-dosing dosing; thus, ease of splitting is critical for this drug product design. Friability Not more than 1.0% No A target of NMT 1.0% mean weight loss is set (whole and w/w according to the compendial requirement and to minimize post-marketing complaints split regarding tablet appearance. This target tablets) friability will not impact patient safety or efficacy. www.drugragulations.org 39
  40. 40. Quality Attributes of the Target Is it a Justification Drug Product CQA?Identification Positive for drug Yes¹ Though identification is critical for safety and substance Z efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity.Assay 100.0% of label claim Yes Variability in assay will affect safety and(whole and split tablets) efficacy; therefore, assay is critical.Content Whole Conforms to USP Yes Variability in content uniformity will affectUniformity Tablet <905> Uniformity of safety and efficacy. Content uniformity of whole and split tablets is critical. Dosage Units Split TabletDegradation Products Individual unknown Yes¹ The limit of degradation products is critical to degradation product: drug product safety. The limit for individual unknown degradation products complies with NMT 0.2% ICH Q3B. A limit for the total degradation Total degradation products is set based on analysis of the RLD products: NMT 1.0% near expiry. The molecular structure of drug substance Z contains no functional groups with obvious sensitivities to oxidation, hydrolysis, acid, base, light or heat and its stability was confirmed in a forced degradation study. No chemical interactions were observed during the development of the IR tablet (ANDA aaaaaa, Section 3.2.P.2.1.2 and Section 3.2.P.8.3 (Appendix I)) or during the excipient compatibility studies performed as part of the development of the MR tablet. Therefore, formulation and process variables are unlikely to impact this CQA. www.drugragulations.org 40
  41. 41. Quality Attributes of the Target Is it a Justification Drug Product CQA?Residual Solvents Conforms to USP Yes¹ The drug substance and excipients used in the <467> drug product formulation contain residual solvents. The limit is critical to drug product safety. However, no organic solvent is used in the drug product manufacturing process and the drug product complies with USP <467> Option 1. This CQA will not be discussed in the pharmaceutical development report but will be considered when setting the raw material acceptance criteria. Whole Similar drug release The drug release profile is important for tablets profile as RLD using a bioavailability (BA) and bioequivalence (BE); therefore, it is critical. Since in vitro drug predictive dissolution release is a surrogate for in vivo performance, method a similar drug release profile to the RLD is targeted to ensure bioequivalence. Split Similar drug release For tablets containing a multi-particulate Yes system, a non-uniform distribution of beads Tablets to whole tablets: f2 >Drug may cause different drug release profiles 50Release between whole and split tablets. Therefore, it is critical and the target is set in accordance with regulatory guidance. Alcohol Comparable or lower The drug release profile in alcohol is critical to Induced drug release patient safety. The target is set to ensure that alcohol stress conditions do not alter Dose compared to the RLD bioavailability of the generic product and Dumping in 5% (v/v), 20% (v/v), introduce additional risks to the patient and 40% (v/v) Alcohol USP in 0.1 N HCl dissolution www.drugragulations.org 41
  42. 42. Quality Attributes of the Target Is it a Justification Drug Product CQA?Water Content Not more than 2.0% No Limited amounts of water in oral solid w/w dosage forms will not impact patient safety or efficacy. Therefore, it is not critical.Microbial Limits Meets relevant Yes¹ Non-compliance with microbial limits will pharmacopoeia impact patient safety. However, as long as raw materials comply with compendial microbial criteria requirements, the formulation and process variables are unlikely to impact this CQA. Water activity will be tested on the final prototype formulation to confirm that the drug product does not support microbial growth. Yes¹:Formulation and process variables are unlikely to impact the CQA. Therefore, the CQA will not be investigated and discussed in detail in subsequent risk assessments and pharmaceutical development. However, the CQA remains a target element of the QTPP and is ensured through the product and process design and the control strategy www.drugragulations.org 42
  43. 43.  For this product, ◦ Physical attributes (size and splitability), ◦ Assay, ◦ Content uniformity (whole and split tablets) and ◦ Drug release (whole tablets, split tablets and alcohol-induced dose dumping) are identified as the subset of CQAs that have the potential to be impacted by the ◦ formulation and/or process variables and, On the other hand, CQAs including ◦ Identity ◦ Degradation products and ◦ Microbial limits which are unlikely to be impacted by ◦ formulation and process variables will not be discussed in detail in the pharmaceutical development report. However, these CQAs are still target elements of the QTPP and are ensured through the product and process design and the control strategy www.drugragulations.org 43
  44. 44. FDA Example :QbD IR Tablet www.drugragulations.org 44
  45. 45. Quality Attributes of the Target Is it a Justification Drug Product CQA?Identification Positive for acetriptan Yes¹ Though identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development.Assay 100.0% of label claim Yes Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout product and process development.Content Conforms to USP Yes Variability in content uniformity will affectUniformity <905> Uniformity of safety and efficacy. Both formulation and process variables impact content uniformity, so Dosage Units this CQA will be evaluated throughout product and process development.Dissolution NLT 80% at 30 Failure to meet the dissolution specification minutes in 900 mL of can impact bioavailability. Both formulation and process variables affect the dissolution 0.1 N HCl with 1.0% profile. This CQA will be investigated w/v SLS using USP throughout formulation and process apparatus 2 at 75 development. rpm www.drugragulations.org 45
  46. 46. Quality Attributes of the Target Is it a Justification Drug Product CQA?Degradation Products ACE12345: Yes Degradation products can impact safety and NMT 0.5%, must be controlled based on compendial/ICH requirements or RLD characterization to limit Any unknown patient exposure. ACE12345 is a common impurity: NMT 0.2%, degradant of acetriptan and its target is based Total impurities: on the level found in near expiry RLD product. NMT 1.0% The limit for total impurities is also based on RLD analysis. The target for any unknown impurity is set according to the ICH identification threshold for this drug product. Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development. Residual solvents can impact safety. However, no solvent is used in the drug product manufacturing process and the drug product complies with USP <467> Option 1. Therefore, formulation and process variables are unlikelyResidual Solvents USP <467> option 1 Yes¹ to impact this CQA. www.drugragulations.org 46
  47. 47. Quality Attributes of the Target Is it a Justification Drug Product CQA?Water Content NMT 4.0% w/w No Generally, water content may affect degradation and microbial growth of the drug product and can be a potential CQA. However, in this case, acetriptan is not sensitive to hydrolysis and moisture will not impact stability.Microbial Limits Meets relevant Yes¹ Non-compliance with microbial limits will pharmacopoeia impact patient safety. However, in this case, the risk of microbial growth is very low because criteria roller compaction (dry granulation) is utilized for this product. Therefore, this CQA will not be discussed in detail during formulation and process development. Yes¹:Formulation and process variables are unlikely to impact the CQA. Therefore, the CQA will not be investigated and discussed in detail in subsequent risk assessments and pharmaceutical development. However, the CQA remains a target element of the QTPP and is ensured through the product and process design and the control strategy www.drugragulations.org 47
  48. 48.  For this product, ◦ Assay, ◦ Content uniformity ◦ Dissolution and ◦ Degradation products are identified as the subset of CQAs that have the potential to be impacted by the ◦ formulation and/or process variables and, Therefore, will be investigated and discussed in detail in subsequent formulation and process development studies. On the other hand, CQAs including identity, ◦ Identity ◦ Residual solvents and ◦ Microbial limits which are unlikely to be impacted by ◦ formulation and process variables will not be discussed in detail in the pharmaceutical development report. However, these CQAs are still target elements of the QTPP and are ensured through the product and process design and the control strategy www.drugragulations.org 48
  49. 49. QbD Now Asks Sponsors to Define their Quality Target Product Profile (QTPP)Asks whether Generic Firms are Focusing Product Design at the Right Target www.drugragulations.org 49
  50. 50. Past / Present QbD Approach ANDA QTPP: Guiding Quality Surrogates Formulation / Used in the process Development of the submitted ANDA Formulation without context and Process Equivalent to the RLD Asks Sponsors HowClaimed to be They Systemicallyacceptable based Arrived at aupon a passing BE Bioequivalent Drugstudy to the RLD Product Bioequivalence by “Bioequivalence by testing Design” www.drugragulations.org 50
  51. 51. Is Formulation Designed using a QTPP that Targets Equivalence to the RLD?Bioequivalence by designFormulation designed based upon If QTPP Surrogate Does not Targetan understanding of critical quality Equivalence to the RLD, may Beattributes to provide equivalent Acceptable. Sponsors Shouldexposure profile needed to achieve Provide Justification Based Onequivalent clinical characteristics in Drug Pharmacokinetic and ClinicalTarget patient population . Profile. www.drugragulations.org 51
  52. 52.  Relationship between risk and criticality: Risk includes severity of harm, probability of occurrence, and detectability, and therefore the level of risk can change as a result of risk management. Quality attribute criticality is primarily based upon severity of harm and does not change as a result of risk management. The identification and linkage of the CQAs should be considered when designing the control strategy. A well-developed control strategy will reduce risk but does not change the criticality of attributes. www.drugragulations.org 52
  53. 53.  CQAs can evolve throughout the product lifecycle, for example: ◦ Change of manufacturing process  change of synthetic route ◦ Subsequent knowledge gained throughout the lifecycle  raw material variability,  pharmacovigilance,  clinical trial experience, and  product complaints www.drugragulations.org 53
  54. 54. 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.drugragulations.org 54

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