QbD Understanding How Excipient Properties Influence Solid Oral Dosage Form Performance

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1 QbD Understanding How Excipient Properties Influence Solid Oral Dosage Form Performance Dr Amina Faham (Dow), Dr Liz Meehan (AstraZeneca) ExcipientFest, Amsterdam NL June 24, 2014

2 What do you understand by the term QbD, in particular applied to excipients? AstraZeneca Do not share without permission

3 Traditional versus QbD approach In traditional approaches, industry focused on: Similar excipient lots are used during development and in commercial manufacturing (avoiding variation) Optimized, fixed formulation and fixed process parameters Compliance with compendial specifications for excipients QbD approach encourages: Understanding variation of excipients properties as they relate to critical process parameters and product quality attributes Building robustness and flexibility into manufacturing process Excipient specifications appropriate to ensure product quality AstraZeneca Do not share without permission

4 Product Quality Attributes Source and Effect/s API Variability Product Variability Excipient Variability Understanding variability & tolerating it = Robustness Process Variability σ 2 Product σ 2 API σ 2 Excipients σ 2 Process σ 2 Interactions Ref: C. Moreton AstraZeneca Do not share without permission 4

5 Excipient functionality and performance Quantitative performance requirements (i.e. critical material attributes) of excipients Characterisation of excipients to determine their suitability for intended use Must be evaluated and controlled to ensure consistent performance throughout the product life-cycle (e.g. changes in suppliers) Integral to the "Quality by Design" approach that should be employed in drug product development AstraZeneca Do not share without permission

6 Quality by Design Spec range CQA Product attributes MSA Drug product Safety and efficacy CPP Process parameters Processing Intermediate attributes CMA API Excipients CMA Material attributes Material attributes CMA AstraZeneca Do not share without permission

7 Quality by Design CQA=Critical quality attributes of the product CMA=Critical material attributes of all input raw materials CPP=Critical process parameters MSA=measurement systems analysis Target Drug Product Profile CQA = f (CMA, CPP) AstraZeneca Do not share without permission

8 Why QbD for excipients? Excipient properties can affect CQAs of drug product Manufacturability (e.g. flow, compaction) Content uniformity (e.g. segregation) Bioavailability (e.g. disintegration, dissolution) Purity Stability (e.g. chemical and physical incompatibilities) It is important to understand and control the effects of excipient variability AstraZeneca Do not share without permission

9 Challenges Excipients developed and manufactured specifically for pharmaceutical use are often available in a range of special grades (developed for specific formulation or process) There are multiple suppliers of nominally the same grade lot-to-lot/batch-to-batch/supplier inequivalence or variability variability in excipient properties should be anticipated and appropriate controls must be in place to ensure consistent performance Excipient applications for pharmaceutical development are many and varied AstraZeneca Do not share without permission

10 Challenges Identification and control of critical material attributes may go beyond monograph specifications and require a thorough understanding of the formulation the process the physical and chemical properties of each ingredient Critical material attributes should be evaluated and controlled to ensure that consistent product performance is achieved throughout the product lifecycle Requires user/supplier collaboration AstraZeneca Do not share without permission

11 Challenges An excipient may have very different functions in the formulation e.g., diluent, lubricant, glidant It may require different performance characteristics e.g., particle size, size distribution, surface area depending on its use in a formulation, manufacturing process, and dosage form. The development, manufacture, and performance of pharmaceutical dosage forms depend heavily upon the physical and chemical properties of the excipients Physical Particle morphology, powder property, polymorph, hygroscopicity, aqueous solubility, pka, and density Chemical Identity, purity, incompatibility with drug substance or other excipients Mechanical Flowability, compressibility AstraZeneca Do not share without permission

12 USP versus PhEur : different approach USP Information Chapter <1059> Excipient Performance Overview of the key functional categories of excipients identified in USP NF. Guidance as to which properties might be important for a particular material in a particular application. Cross-references to standard methods that can be used by both manufacturers and users: Makes communication more straightforward Avoids an unnecessary plethora of test variations for a particular parameter. Keeping the tests non-mandatory. Avoiding confusion with mandatory tests and labelling tests. Not imposing limits/specifications. AstraZeneca Do not share without permission

13 Extract from USP <1059> Not all critical material attributes of an excipient may be identified or evaluated by tests, procedures, and acceptance criteria in NF monographs. Excipient suppliers and users therefore at times may wish to identify and control critical excipient attributes that go beyond monograph specifications. AstraZeneca Do not share without permission

14 USP versus PhEur : different approach PhEur Within each individual excipient monograph a section exists for non-mandatory Functionality Related Characteristics (FRCs) that should be considered e.g. Croscarmellose sodium Settling volume Degree of substitution Particle size distribution Hausner ratio e.g. Dibasic Calcium Phosphate Particle size distribution Bulk and tapped density Powder flow AstraZeneca Do not share without permission

15 Excipient variability how much do you need to do? A risk based approach benefits both the patient and the business Not all excipients have an impact on product quality or safety Not all properties of an excipient are equally important In many cases normal excipient variation does not negatively impact the quality and safety of the product The way forward Comprehensive studies of excipient properties are only needed when the excipient properties are expected to impact the critical quality attributes (CQAs) of the drug product The goal is to define control strategy for excipients AstraZeneca Do not share without permission

16 Case study to exemplify the approach Microcrystalline cellulose Degree of polymerisation ph Bulk density Loss on drying Residue on ignition Conductivity Ether soluble substances Water soluble substances Impurities Particle size distribution Mannitol Conductivity Loss on drying Reducing sugars Assay Particle size distribution Porosity/Specific surface area Bulk density Polymorphic form Impurities Sodium starch glycolate ph Loss on drying Sodium chloride Sodium glycolate Assay (Na) Bulk density Rate/degree of swelling Magnesium stearate Particle size Specific surface area Loss on drying Stearic/palmitic acid level Assay (Mg) To explore every material attribute would require many thousands of experiments Risk assessment is required to focus the experimental programme AstraZeneca Do not share without permission

17 Assessing the risk of excipient variability Collect existing data/information on the raw materials Excipient monographs, literature examples, Handbook of Pharmaceutical Excipients, supplier certificates of analysis, supplier databases, etc Refer to target product profile target patient populations, geographical markets, etc For each excipient in the formulation, identify potential critical material attributes (functionality) and potential risk factors (security of supply, commercial and regulatory considerations) Score the potential risk for each material attribute and risk factor AstraZeneca Do not share without permission

18 Possible outcome after risk assessment Microcrystalline cellulose Degree of polymerisation ph Bulk density Loss on drying Residue on ignition Conductivity Ether soluble substances Water soluble substances Impurities Particle size distribution Mannitol Conductivity Loss on drying Reducing sugars Assay Particle size distribution Porosity/Specific surface area Bulk density Polymorphic form Impurities Sodium starch glycolate ph Loss on drying Sodium chloride Sodium glycolate Assay (Na) Bulk density Rate/degree of swelling Magnesium stearate Particle size Specific surface area Loss on drying Stearic/palmitic acid level Assay (Mg) Risk assessment reduces the number of potential CMAs to consider for experimental work Some material attributes could be confounded providing further simplification AstraZeneca Do not share without permission

19 Next steps Risk assessment scores identify the highest risks excipient attributes Select/source excipient variants Batch select from a particular supplier and within grade (QbD sample sets) From one supplier use different grades (more extreme variation) From multiple suppliers (different ranges of variation) Perform risk mitigation work to study effect of excipient variability (on process and/or product performance) Use outputs to define excipient control strategy AstraZeneca Do not share without permission

20 Excipient supplier-user collaboration Exchange of information between excipient supplier and user is invaluable Provides benefits to both supplier and user IPEC QbD checklists developed to help facilitate this Available to IPEC Europe members as downloads from the website AstraZeneca Do not share without permission

21 IPEC QbD checklists For suppliers For Users AstraZeneca Do not share without permission

22 How HPMC Physicochemical Properties Impact Matrix Tablet Performance ExcipientFest, Amsterdam NL June 24, 2014

23 Outline Background and HPMC materials HPMC physical properties and how they impact matrix tablet performance HPMC chemical properties and how they impact matrix tablet performance 23

24 Quality by Design (QbD) Means Design the Product And The Process Design the product to meet patient requirements Design the process to consistently meet product critical quality attributes Understand the impact of starting materials and process parameters on product quality Identify and control the source of process variation Continually monitor and update the process to allow a consistent quality over time

25 Quality by Design (QbD) The drug product must be safe and efficacious for the patient. I.e., Ensure the dosage form performs as expected. How robust is dosage form performance? How robust is the process to make the dosage form? How robust are the methods to characterize the dosage form? What is the impact of raw material variability? (API? Excipients?) Multiple suppliers? Lot-to-lot variability? 27

26 Properties vs. Performance Raw material properties Physical Chemical Process Processability E.g. Flowability Process steps and parameters which are critical to quality. Performance Dosage form physical properties Achieving desired performance API release Is desired performance reproducible (e.g. from lot-to-lot, day-to-day)? 28

27 HPMC Matrix Tablets for Modified-Release Hydrophilic matrix tablets are the most commonly utilized MR dosage form. Simplest. Fastest to develop. Least expensive to manufacture. Hypromellose 2208 is the most common rate-modifying excipient used in hydrophilic matrices. OCH 3 O O HO HO O OCH 3 OH OH OCH OCH 3 O 3 O HO O HO O O O O OH O O CH 3 O OCH OCH 3 3 R = CH 3 OH R 29

28 HPMC Sustained Release Matrix Tablets Key Hypromellose Formulation Variables Level Molecular weight/viscosity Substitution type Particle size distribution Actives and other excipients can cause the formulation to be more sensitive to HPMC properties

29 How HPMC Physical Properties Impact Matrix Tablet Performance 31

30 Hypromellose Level For a selected hypromellose product, polymer level is usually the major drug release rate controlling factor Ford et al IJP, 24: and Drug release may be more sensitive to variations in hypromellose properties at low hypromellose levels (< 30%) 10% propranolol HCl, METHOCEL K4M balance lactose, 0.5% mag stearate 32

31 Particle Size 33

32 Drug Released (%) Particle Size caffeine (50%), K15M (30%) - 6 hr metoprolol tartrate (20%), K4M (30%) - 3 hr theophylline (50%), K4M (30%) - 6 hr HPMC Particle Size (% thru 230 mesh) 34

33 Drug Released (%) Particle Size acetaminophen (50%), K100M (30%) - 6 hr hydrochlorothiazide (50%), K100 LV (30%) - 3 hr ketoprofen (20%), K4M (30%) - 12 hr HPMC Particle Size (% thru 230 mesh) 35

34 % PP dissolved METHOCEL K15M Premium CR Propranolol HCl release: effect of particle size f 2 = f 2 = Time (min) High % thru 230 mesh/ Low Level Low % thru 230 mesh/ Low Level Center Point/ Low Level High % thru 230 mesh/ High Level Low % thru 230 mesh/ High Level Center Point/ High Level Higher polymer level slower drug release Higher polymer level lower variability Drug release were significantly affected by coarser P/S for lower polymer level 36

35 How HPMC Chemical Properties Impact Matrix Tablet Performance 37

36 Selection of Hypromellose substitution grade Hypromellose grade has a significant effect on dissolution Methylcellulose and Hypromellose 2906 (A and F Chemistry) typically are not used for CR applications 38

37 % PP dissolved METHOCEL K15M Premium CR Propranolol HCl release: effect of viscosity f 2 = f 2 = Time (min) High Viscosity/ Low Level Low Viscosity/ Low Level Center Point/ Low Level High Viscosity/ High Level Low Viscosity/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Higher polymer level lower variability Drug release were consistent across viscosity range 39

38 Hypromellose Substitution 50% diclofenac sodium, 40% METHOCEL K15M 9.5% lactose, 0.5% mag stearate 40% salicylic acid, 30% METHOCEL K15M 29% lactose, 1% mag stearate 40

39 Paracetamol Model Example Ingredient % w/w Weight per tablet (mg) Paracetamol* METHOCEL K4M or Pilot Plant HPMC Lactose Magnesium stearate 1 5 Talc 1 5 Total Actual tablet weight: 502 ± 3 mg Hardness: 94 ± 8 N * Paracetamol: Analgesic Aqueous solubility: 14 mg/ml

40 Paracetamol Released (%) Batch-to-Batch Consistency Batch-to-batch consistency with commercial METHOCEL : Reproducible modified-release performance Time(min) Batch no. 1 Batch no. 2 Batch no. 3 Batch no. 4 Batch no. 5 Batch no. 6 Batch no. 7 Batch no. 8 Batch no. 9 Batch no. 10 Batch no. 11 Batch no. 12 Batch no. 13 Batch no. 14 Batch no. 15 Batch no. 16 Batch no. 17 Batch no. 18 Batch no. 19 Batch no. 20 Rogers TL, Petermann O, Adden R, and Knarr M (2011). Investigation and rank -ordering of hypromellose 2208 properties impacting modified release performance of a hydrophilic matrix tablet, Twenty-Sixth Annual Meeting, Proceedings of the American Association of Pharmaceutical Scientists, Washington DC, Poster no. R ml ph 5.7 phosphate buffer at 37 C 50 rpm paddle speed Tablets placed in sinkers n=6 standard deviation was never more than 2% 50% Cumulative Volume Particle Size (µm) Commercial Batch No. %Me %HP %NaCl Average Std Deviation % Viscosity (mpa s) 42

41 METHOCEL FRCs Impacting Performance ESTABLISHING THE PERFORMANCE DESIGN SPACE Based on this model, rank-order of METHOCEL FRC impact is as follows: %HP (p < 0.05) > 2% viscosity (p = 0.06) > particle size (p = 0.13) > %Me (p = 0.75). Correlations between paracetamol release and HP substitution vs. 2% viscosity reflect findings from the model. Paracetamol release increases with increasing HP content. Trend occurs over a narrow range of 79-86% paracetamol released at 22 hr, reflecting reproducible batch-to-batch modified-release performance. Rogers TL, Petermann O, Adden R, and Knarr M (2011). Investigation and rank -ordering of hypromellose 2208 properties impacting modified release performance of a hydrophilic matrix tablet, Twenty-Sixth Annual Meeting, Proceedings of the American Association of Pharmaceutical Scientists, Washington DC, Poster no. R

42 HP Content (%) Pilot Plant HPMC vs. Commercial METHOCEL Expanded design space boundaries with pilot plant HPMC. HP substitution was purposefully varied. Premise: There is insufficient batch-to-batch variability in commercial METHOCEL to investigate performance design space proactively. We cannot explore the allowable pharmacopeial design space. Where are the boundaries of robustness? What if we miss optimal performance sweet spots? Breadth of minimum and maximum HP content (4 12%) according to the harmonized pharmacopeia (USP, PhEur, and JP). Commercial Batches 1 through 21 Pilot Plant Batches 1 through 9 Sample identification %Me %HP 50% cumulative volume particle size (µm) %NaCl 2% viscosity (mpa-s) See previous section for FRCs of commercial batches investigated Prototype No Prototype No Prototype No Prototype No < Prototype No Prototype No < Prototype No < Prototype No < Prototype No < Rogers TL, Knarr M, Petermann O, and Adden R (2011). Expanding design space boundaries within pharmacopeial limits: Impact of atypical hydroxypropoxyl substitution on drug release from HPMC matrices, Twenty-Sixth Annual Meeting, Proceedings of the American Association of Pharmaceutical Scientists, Washington DC, Poster no. R

43 Modified-Release Performance Pilot plant HPMC data brackets commercial METHOCEL data for HP substitution and paracetamol release. Paracetamol release increases with increasing HP substitution. Efficiently determined that formulation is robust. Rogers TL, Knarr M, Petermann O, and Adden R (2011). Expanding design space boundaries within pharmacopeial limits: Impact of atypical hydroxypropoxyl substitution on drug release from HPMC matrices, Twenty-Sixth Annual Meeting, Proceedings of the American Association of Pharmaceutical Scientists, Washington DC, Poster no. R6167.

44 Indapamide Example Ingredient % w/w Weight per tablet (mg) Indapamide* Pilot Plant HPMC Lactose Microcrystalline cellulose Magnesium stearate Talc Total Actual tablet weight: 200 ± 3 mg Hardness: 83 ± 8 N Friability: Weight loss 0.16% * Indapamide: Antihypertensive Aqueous solubility: 75 µg/ml

45 Indapamide Released (%) Modified-Release Performance Only variable was the HPMC batch used. Same formulation composition. Tried to hold everything constant except HPMC batch % indapamide released at 17 hr ranged from 60 to 90% 0.1% SLS in 900 ml water at 37 C 50 rpm paddle speed Tablets placed in hanging baskets n=6 standard deviation was never more than 5% 20 0 Breaking point in modified release performance Time (min) Step-change increase in API release Proactively determined that API and formulation are very sensitive to variation in %HP substitution. High risk of batch failure. 47

46 Performance Design Space Modulation of API release spans of ~35% Potential extent of variation unacceptable Proactive exploration of design space identified highly responsive API Breaking point in modified release performance Above HP content of 7.8% HPMC specification recommended Step-change increase in API release

47 Summary Modified release performance is most significantly impacted by HP substitution of METHOCEL HP substitution is the primary factor modulating modified release Forced-variation prototypes enabled expansion of the design space boundaries of our model formulation APIs highly responsive to METHOCEL FRCs 49

48 Questions? Thank You! 11/24/11