3. Drug or plant or excipients profile

Transcription

1 3. Drug or plant or excipients profile 3. 1 Analysis of Reference Listed Drug (RLD) Product ABILIFY (aripiprazole) Clinical The Reference Listed Drug (RLD) is Brand ABILIFY (aripiprazole) Tablets 2mg, 5mg, 10mg, 15mg, 20mg & 30mg and was approved by the USFDA for treatment of schizophrenia on November 15, 2002 (NDA ), for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004, and as an adjunct for major depressive disorder on November 20, The RLD is 10 mg strength (IR) tablet is uncoated tablet. The daily dose of ABILIFY (aripiprazole) in the label is 30 mg Pharmacokinetics Aripiprazole, after oral administration it is poorly absorbed. The median Tmax is 3-5 hours (h) in patients. The mean absolute bioavailability of Aripiprazole is approximately 87%. Administration of a 15mg ABILIFY (aripiprazole) tablet with a standard high fat meal did not significantly affect the AUC or Cmax of ABILIFY (aripiprazole) or its active metabolite, dehydro-aripiprazole but delayed Tmax by 3 hours for Aripiprazole and 12 hours for dehydro-aripiprazole. The mean elimination half-lives for ABILIFY (aripiprazole) and dehydro-aripiprazole are about 75 hours and 94 hours respectively. Activity of ABILIFY (aripiprazole) is mainely due to the parent drug, Aripiprazole, and to a same extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D 2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. Within 14 days of dosing both ABILIFY (aripiprazole) and dehydro-aripiprazole, steady state plasma concentrations are attained. Accumulatioon of aripiprazole is predictable from single-dose pharmacokinetics. The pharmacokinetics of aripiprazole is dose proportional at steady state plasma concentration. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. 79

2 3.1.3 Components of Drug Product Drug substance A. Physical properties Physical description: The following physical description is for Aripiprazole In-House, which is Form B (Anhydrous Aripiprazole). Appearance: White to off-white crystalline powder. Particle size distribution: PSD of drug substance (B. no. PP110301) was measured using Malvern Mastersizer. The results were as follows: D (0.9) µm (NMT 25µ). This is representative of the drug substance PSD selected for the final drug product formulation. Solid-state form: To date, WO 03/ discloses at least nine crystal forms, including anhydrate and anhydrous forms, such as type-i and type II & WO 03/ discloses anhydride crystal form B, C, D, E, F, G and hydrate A of Aripiprazole. The DMF holder provides Aripiprazole polymorphic form B consistently based on in-house batch analysis data obtained by XRD. Melting point: C Aqueous solubility as a function of ph: The solubility of aripiprazole in aqueous media as a function of ph was determined. Aripiprazole is practically insoluble in water. However, it is a base, with pka of 7.6 and has a ph-dependent solubility profile. Hygroscopicity: Aripiprazole form B is non-hygroscopic and no special protection is required from humidity during handling, shipping or storage. Hygroscopicity studies were carried out in dessicator and room environment conditions for both API and tablets. The temperature was maintained at 25 0 C. Density: The bulk, tapped density, as well as the flowability of Aripiprazole form B (PP110301) was measured. Tapped bulk density (BD): 0.43 g/ml 80

3 B. Chemical Properties pka: Aripiprazole is a base with pka of 7.6. C. Stability Studies Aripiprazole tablets were subjected to different stress stability conditions as per the ICH guidelines. D. Biological Properties Partition coefficient: Log P 4.5 Bio pharmaceutics classification: From the Summary basis of approval, the data support the categorization of Aripiprazole as a BCS class IV compound (low solubility and low permeability). E. Risk assessment of drug substance attributes 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 outcome of the assessment and the accompanying justification is provided as a summary in the pharmaceutical development report. The relative risk that each attribute presents was ranked as low, medium and high. The high risk attributes warranted further investigation whereas the low-risk attributes required 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. The same relative risk ranking system was used throughout pharmaceutical development and is summarized in Table No. 9. Table No. 9: Overview of relative Risk Ranking System 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 Based upon the physical, chemical and biological properties of the drug substance, the initial risk assessment of drug substance attributes on drug product CQAs is shown in Table No

4 Table No. 10: Initial Risk Assessment of the Drug substance attributes: Drug Drug substance Attributes product CQAs Solid state form PSD Hygroscopicit y Solu bilit y Moisture content Residual solvents Process impuriti es Chemica l stability Flow properti es Assay Low Low Low Low Low Low Low High Medium Low Medium Low Low Low Low Low Low High uniformi ty Dissolut High High Low High Low Low Low Medium Low ion Degrada tion product High Low Low Low Low Low Low Low Low Table No. 11: Justification for the initial risk assessment of the drug substance attributes. Drug substance attributes Drug CQAs Justification Solid state form Assay Drug solid state form does not affect tablet assay and CU. The risk is low. Dissolution Diff. Polymorphic forms of the drug have diff solubility and can impact dissolution. The risk is high. Drug with diff polymorphic forms have different chemical stability & may affect degradation of tablet. The risk is high. Particle size Assay As the PSD has been fixed. The risk is low. distribution (PSD) PSD has direct impact on flowability and ultimately CU. Due to the fact that the drug substance is milled, the risk is high. 82

5 Drug substance attributes Hygroscopicity Solubility Moisture content Residual solvents Drug CQAs Dissolution Assay Dissolution Assay Dissolution Assay Dissolution Assay Dissolution Justification The drug is BCS class IV compound, therefore PSD can affect dissolution. The risk is high. The stability for selected PSD has been evaluated during DMF. The micronized drug substance is stable during stability. The risk is low. Aripiprazole is not hygroscopic. The risk is low. Solubility does not affect tablet assay, CU, degradation properties. Aripiprazole exhibited low solubility, which strongly impacts the dissolution. The risk is high. Moisture is controlled in the drug substance specification (NMT 0.5% w/w). Thus, it is unlikely to impact assay, CU, dissolution, degradation. The risk is low. Residual solvents are controlled in the drug substance specification and comply with USP<467>. At ppm level residual solvents are unlikely to impact assay, CU, dissolution. The risk is low. are unlikely to form in the presence of PPM levels of residual solvents. The risk is low 83

6 Drug Drug Justification substance attributes CQAs Process Assay Total impurities are controlled in the drug substance impurities Dissolution specification (NMT 1.0%). Impurity limits comply with ICH Q3A recommendations. Within this range process impurities are unlikely to impact assay, CU, dissolution. The risk is low. The likely hood of process impurities to increase in formulation is less. The risk is low. Chemical stability Assay The drug substance is susceptible to oxidative degradation; therefore Aripiprazole Chemical stability may affect drug product Assay and degradation. The risk is high. Tablet is unrelated to drug substance chemical stability. The risk is low. Dissolution Tablet dissolution is dependant on the form of Aripiprazole in tablet. There are chances of conversion of Aripiprazole to its monohydrate salt which has less solubility as compared to anhydrous form this may effect the tablet dissolution. The risk is medium. There is only one degradation product identified as of now. The limits are as per ICH guidelines. The risk is low Flow properties Assay Aripiprazole has poor flow properties. In extreme cases, poor flow may impact assay. The risk is medium. Aripiprazole has poor flow properties which may lead to poor tablet CU. The risk is high. Dissolution The flowability of the drug substance is not related to its degradation pathway or solubility. The risk is low Excipients For the preparation of Aripiprazole tablets, same excipients were selected as used in the RLD, excipient compatibility studies and prior use in approved ANDA 84

7 that utilize wet granulation. A summary of the Excipient-drug substance compatibility studies and the selection of each excipient grade is provided in the following section. Excipients compatibility studies Excipient-drug substance compatibility was assessed through HPLC analysis of binary mixtures of Excipient and drug substance in different ratios in the solid state. Samples were stored at 25 0 C/60%RH and 40 0 C/75%RH in closed containers for 1 month. Common excipients used as filler, disintegrants and lubricant were evaluated in the excipient compatibility study. Table No. 17 summarizes the results. Excipients grade selection On the basis of Excipient compatibility studies, Excipients similar to the RLD formulation were selected for the generic product development. Excipient grade and supplier was selected on the basis of previous formulation experience and knowledge about excipients that have been used successfully in approved manufactured by wet granulation as given in Table No. 9. The levels of excipients used in the formulation were studied in subsequent formulation development studies. Table No. 12: Initial selection of excipient type, grade and supplier Excipient Supplier Grade Lactose monohydrate (pharmatose DFE Pharma Pharmatose 200 M 200M) Microcrystalline cellulose (MCC) FMC Biopolymer Avicel PH101 Corn starch (unipure FL) National starch Unipure FL Low substituted hydroxyl propyl ShinEtsu L HPC LH-21 cellulose Microcrystalline cellulose (MCC) FMC Biopolymer Avicel PH112 Pigment blend Green Colorcon PB-1543 FD&C Blue #2 Al 11%-14% Colorcon - Iron Oxide Red (Sicovit red 30) Rockwood Sicovit Red 30 Iron Oxide Yellow (Sicovit yellow 10) Rockwood Sicovit Yellow 10 Magnesium stearate (Hyqual) Mallinckrodt - 85

8 Total Drug composition about 80% comprises with MCC and lactose monohydrate. Commonly used fillers in wet granulation process are mainly microcrystalline cellulose and lactose monohydrate in combination or individually. They are having good compression properties as well as good flow properties. The particle size distribution, particle morphology, aspect ratio, bulk density and flowability of different grades have the potential to affect drug product content. Therefore, additional particle size controls above those in the pharmacopoeia are included in the specifications for the two major excipients: lactose monohydrate D (0.9) µm and microcrystalline cellulose (D (0.5) µm). The specifications mentioned for fillers are used in further formulation studies. Lactose monohydrate (Pharmatose 200M): In wet granulation as filler is mostly used that is lactose monohydrate. Lactose monohydrate having two impurities aldehydes and melanine. The supplier has certified that the lactose is free of melamine and has provided a certificate of suitability for TSE/BSE. Lactose monohydrate Grade Pharmatose 200M from DMV International was selected based on successful product development in earlier approved ANDAs, where the wet granulation process was used. The selected grade provides acceptable flow and compression properties when used in combination with microcrystalline cellulose. Microcrystalline cellulose (MCC): Micro crystalline cellulose is mostly used in direct compression, wet granulation and roller compaction as filler. Though it is reported in the literature that MCC may physically bind or adsorb drug molecules, but no evident was found in dissolution studies. Only few grades of MCC are suitable for wet granulation. MCC Grade Avicel PH 101 from FMC Biopolymer was selected based on its suitability for wet granulation when used in combination with lactose monohydrate as demonstrated in earlier approved ANDAs. Corn starch (unipure FL): Aripiprazole is a BCS class IV drug so rapid disintegration is necessary to ensure maximum bioavailability. Corn starch is widely used as disintegrant for wet granulation. Corn starch having good swelling capacity, as it swells about 4-8 times than its original structure when combined with water. Grade Unipure FL from National Starch was selected. 86

9 Low substituted hydroxyl propyl cellulose: Low substituted Hydroxypropyl cellulose is used as a disintegrant and/or binder both intragranularly and extragranularly in the formulation. L HPC LH-21 from Shin- etsu chemical co ltd. Japan was selected. Magnesium stearate: The frequently used lubricant for tablets is magnesium stearate. Hyqual (Magnesium stearate) from Mallinckrodt was selected and is of vegetable origin Drug substance particle size selection for product development In general, for drug substance with particle size in the micrometer range, a larger drug substance particle size improves manufacturability because it has better flow. However, for a BCS IV compound like Aripiprazole, larger drug substance particle size may significantly decrease dissolution and negatively impact the in vivo performance. With an aim to identify the appropriate drug substance particle size distribution range for further study, a prototype formulation was designed to identify the impact of the drug substance mean particle size, D (0.9), on the dissolution between the test product and the RLD. The data indicate that a D(0.9) of 30um or less met the predefined criterion when compared to the RLD Process selection When D (0.9) is in the range of µm, Aripiprazole is cohesive and displays poor flow ability as evidenced by the compressibility index, Hausner ratio. variability and high tablet weight produced because uneven distribution of drug substance in the blend, uneven filling of die cavities on the tablet press. Poor Aripiprazole flow rules out the use of a high drug load formulation and supports the use of a similar drug load to the RLD. Most common processes for tablet manufacturing include direct compression, dry granulation & wet granulation. Direct compression was planned but eliminated based on the reasons that the formulation has low concentration of API and there may be a chance of poor distribution of the API. 87

10 Drug substance was not temperature sensitive it is confirmed by force degradation studies based on that wet granulation was selected as the process. And wet granulation provided good flow of granules and good compressibility. Based on this wet granulation process was found satisfactory and this strategy was finalized Development of Aripiprazole Tablets started with wet granulation as tablet manufacturing process with 2 mg, 5mg, 10mg tablets are essentially proportionally similar i.e the total tablet weight is the same with the only change being the amount of drug with a corresponding change in the amount of lactose and the presence of a different colorant respectively for each strength. The other strengths 15mg, 20 mg, 30 tablets are dose proportional to 10mg strength with corresponding change in the colorant for each strength. 3.2 Analysis of Reference Listed Drug (RLD) Product Effexor XR Innovator (Wyeth Pharmaceuticals) markets the drug product under the brand name of Effexor XR. Evaluation of Effexor was performed in manner similar to Aripiprazole Excipients: Process of selection of excipients has been based on the design and fabrication of the extended release dosage form, their compatibility with drug substance and their intended functions, so that the in-vivo and in-vitro performance of the proposed formulation is comparable to that of the reference product. The excipients used were all GRAS listed and within IIG limits. The list is mentioned in Table No. 143 Choice of excipients, their grades based on intended functions The following excipients were used in the proposed formulations, which were suitable to the dosage form, formulation process, intended characteristics and quality attributes. All the excipients were sourced from reputed manufacturer's their quality complies as per the compendial requirements (USP) and other in-house quality attributes. 88

11 Moreover, all the excipients were compatible with the drug substance as detailed further in this section. Drug-Excipient compatibility studies: Compatibility screening of a number of commonly used excipients was performed at the early pre-formulation stage of development to obtain information regarding potential incompatibilities between Venlafaxine Hydrochloride and excipients. The drug along with different excipients was mixed, sealed in clear glass vials with LDPE stoppers and charged into stability chambers at 40 C± 2 C/ 75 % ± 5% RH and 25 C± 2 C/ 60% ± 5% RH. These vials were inspected periodically for 4 weeks to observe any physical change in appearance. The observations are tabulated in the results and discussion section. Table No. 144 shows the drug-excipient compatibility Excipients Concentration:- The levels of inactive ingredients used in the formulation conform to the reported levels as per USFDA's Inactive Ingredient's [IIG] database: Table no 13: List of IIG used Sr. No. Ingredients Amount (in mg) per unit of Venlafaxine HCl ER Capsules, 150 mg Maximum Potency as per II G (oral route) Maximum Potency as per IIG (oral route, ER) 1 Microcrystalline I mg mg, (oral, cellulose NF (PH 101) tablet, ER) 2 Povidone USP (K 30) mg mg (oral, capsule, SR) 3 Ethyl cellulose NF mg 39.2 mg (N50) 4 Triethyl citrate NF mg 5 Acryl-EZE MP * * white 6 Talc USP Capsule Shell - ** * 89

12 All the individual components of Acryl-EZE MP white also comply as per IIG levels by oral route. All the individual components of capsule shell complies as per IIG levels by oral route. Ferric oxide used in imprinting ink (red ink) on the capsule shells used in Venlafaxine HCl ER capsules of 37.5 mg and 75 mg strength complies to maximum daily dose of iron (Not more than 5. 0 mg/day). Table no 14. Acryl-EZE MP white Component % w/w as per Maximum amount in mg IIG levels (mg) supplier certificate per capsules of 150 mg (oral ER) Methacrylic acid copolymer Talc Triethyl citrate Sodium bicarbonate Colloidal anhydrous silica Sodium Lauryl sulfate Table No. 15. Capsules Shell for Venlafaxine Hydrochloride Extended Release capsules, 37.5 mg Component % w/w as per mg/capsule IIG levels (mg) (oral supplier certificate route) D&C red# mg FD&C blue #I mg FD&C yellow # mg (dye F.D&C yellow #6) I3.3 mg-lake Titanium dioxide mg Gelatin q.s mg FDA/EI72 black iron oxide mg (Ferric oxide red) 90

13 Table No. 16. Capsules Shell for Venlafaxine Hydrochloride Extended Release capsules, 75 mg Component % w/w as per mg/capsule IIG levels (mg) (oral supplier certificate route) D&C red# mg FD&C blue #I mg FD&C yellow # mg (dye F.D&C yellow #6) I3.3 mg-lake Titanium dioxide mg Gelatin q.s mg Table No. 17. Capsules Shell for Venlafaxine Hydrochloride Extended Release capsules, 150 mg Component % w/w as per mg/capsule IIG levels (mg) (oral supplier certificate route) FD&C blue #I mg FD&C yellow # mg (dye FD&C yellow #5) I2.42 mg-lake FD&C yellow # mg (dye F.D&C yellow #6) I3.3 mg-lake Titanium dioxide mg Gelatin q.s mg Calculation for amount of iron oxide per capsule in Venlafaxine hydrochloride extended release capsules 35mg a) Amount of black iron oxide per capsule = % w/w (as a component of capsule shell) Average weight of size 2" capsule shell = 61 mg So amount of black iron oxide /capsule = 0.49 mg (a) Amount of imprinting ink used /capsule # = 0.02 mg (# Declaration from capsule shell refer enclosed) 91

14 b) Maximum amount of red iron oxide in imprinting ink " = 22%w/w So, amount of red iron oxide /capsule = 22/100*0.02 mg = mg (b) Total iron oxide /capsule = a+b = = mg Molecular weight of iron oxide (Fe 2 O 3 ) = mg of iron (2x.Fe) in iron oxide: Hence iron content/capsule = / *0.494 =0.35 mg The chart below as an average value for the amount of ink on a capsule, actual amount will vary lightly due to log difference. Table No. 18 Iron content Radially Radially Printed Capsule Size Amount/1000 capsule 0/0EL mg mg mg mg mg Supra A 72.0 mg mg Table No. 19: Iron content Axially Axial printed capsule Size Amount/1000 capsule 0/ 0EL 33.2 mg mg mg mg mg mg 92