Chapter Exprimental methods - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/64163/15... · Granulation end point Granulation Dissolution Blending Time Blending Tablets Hardness

Exprimental methods Chapter V

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Department of Pharmaceutical sciences JJTU JHUNJHUNU

Diagram 1: Flow Diagram of desired product quality.

Drug substance

Related substances

API assay

Purity Potency

Particle Size Uniformity

Granulation Granulation end point

Dissolution

Blending Blending Time

Tablets

Hardness & Disintegration time

Weight Variation, Friability Tablet Characteristics

Stability

Raw Materials and Manufacturing

Critical Quality Attributes

Desired Product Quality


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Preformulation Studies:

Preformulation testing is the first step in the rationale development of dosage forms

of a drug substance. It can be defined as an investigation of physical and chemical

properties of a drug substance alone and when combined with excipients. The overall

objective of preformulation testing is to generate information useful to the formulator in

developing stable and bioavailable dosage forms, which can be mass- produced. Following

preformulation studies were performed.

PREFORMULATION STUDIES OF PURE DRUG:

Identification of pure drug:

Identification of Memantine Hydrochloride was carried out by IR spectrum, DSC and

X-ray powder pattern

Melting point determination:

Melting point of Memantine Hydrochloride was determined by Open capillary method.

Bulk Density:

a) Loose Bulk Density: Accurately weighed 5 g of drug (M), which was previously

passed through 20 # sieve, was transferred in 50 ml graduated cylinder. The powder in

the cylinder was leveled without compacting, and the unsettled apparent volume (V0)

was noted. The apparent bulk density (gm/ml) was calculated by the following formula

Bulk density = Weight of powder / Bulk volume …………. (1)

b ) Tapped bulk density: Accurately weighed 5g of drug, which was previously

passed through 20 # sieve, was transferred in 50 ml graduated cylinder. Then the

cylinder containing the sample was mechanically tapped by raising the cylinder and

allowing it to drop under its own weight using mechanically tapped density tester that


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provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute. The

cylinder was tapped 500 times initially and the tapped volume (V1) was measured to

the nearest graduated units, the tapping was repeated an additional 750 times and the

tapped volume (V2) was measured to the nearest graduated units. If the difference

between two volumes is less than 2% then the final olume V2). The tapped bulk

density in gm/ml was calculated by the following formula:

Tapped Density = Weight of powder / Tapped volume …….. (2)

Particle Size Analysis

Particle size of drug was determined by Malvern particle size analyzer. D (10,

13.42), D (50, 55.32), D (90, 149.21).

Solubility Analysis

A semi quantitative determination of solubility can be made by adding a solute in small

incremental amounts to fixed volume of solvents whose pH ranging from 1.2 to 7.4 including

distilled water. After each addition, the system is vigorously shaken and examined usually for

any undissolved particles. When some solute remains undissolved the total amount added up to

that point serves as a good and rapid estimate of solid.

Dissolution media of Memantine Hydrochloride Tablets:

The dissolution media is recommended by OGD, USFDA for in-vitro release studies of

Memantine Hydrochloride Tablets.

Drug - excipient Compatibility Studies:

A successful formulation of a stable and effective solid dosage form depends on

careful selection of excipients that are added to facilitate administration, promote the

consistent release and bioavailability of the drug and protect it from degradation. If the

excipients are new and not been used in formulation containing the active substance, the

compatibility studies are of paramount importance.


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Development of Memantine Hydrochloride Tablets 10 mg was planned based on literature of

API, Marketed dosage form details and preformulation data, excipients and developmental

process was selected.

Initially, the quality target product profile (QTPP) was defined based on the properties of the

drug substance, characterization of the Reference Product and consideration of the Reference

Product label and intended patient population. Identification of critical quality attributes (CQAs)

was on the basis of the severity of harmful to a patient (safety and efficacy) resulting from failure

to meet that quality attribute of the drug product. Our investigation during pharmaceutical

development focused on those CQAs that could be impacted by a realistic change to the

drug product formulation or manufacturing process. For these CQAs included assay, content

uniformity, drug release and degradation products.

Based on the available literature and pH dependent solubility data, Memantine Hydrochloride

shows Class I i.e. high solubility and high permeability. Risk assessment was used whole

development to find potential high risk on the formulation, process variables. To identify which

studies were necessary to get product, process understanding in order to formulate a control

strategy. Every risk assessment was then updated after formulation development to see the

reduced risk level depend on our enhanced product, process understanding.

Table No. 1 Initial assessment of risk for drug substance attributes

Drug Produ

ct CQAs

Drug Substance Attributes

Solid State Form

Particle Size

Distribu tion

(PSD)

Hygroscopi

city

Solubil ity

Loss on

Dryin g

Residu al

Solvent s

Process Impuriti

es

Chemi cal

Stabilit y

Flow

Propertie s

Assay

Low

Mediu m

Low

Low

Low

Low

Low

Low

Medium

Content Uniformity

Low Mediu

m

Low

Low

Low

Low

Low

Low

High

Dissolution

Low

Low

Low

Low

Low

Low

Low

Low Low

Degradatio n

Products

Low

Low

Low

Low

Low

Low

Low

Low

Low


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Table No. 2 Justification for the Initial assessment of risk for drug substance attributes


Drug Products CQAs

Justification

Solid State Form

Assay Drug substance solid state form does not affect tablet assay and CU. The risk is low Content Uniformity

Dissolution Memantine HCl is highly soluble compound; therefore, it does not affect Dissolution. The risk is low.

Degradation Products crystalli ne form of the drug substance represents that Memantine HCl is a stable molecule. The risk is low.

Particle Size Distribution (PSD)

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 impact on CU. Due to the fact that the manufacturing process is a wet granulation method, hence risk is considered as medium.

Dissolution Memantine HCl is highly soluble compound; therefore, it does not affect Dissolution. The risk is Low.

Degradation Products The representative PSD of drug substance is stable as per the DMF, hence the risk is low.

Hygroscopicity

Assay Memantine HCl is non-hygroscopic. The risk is low.

Content Uniformity Dissolution Degradation Products

Solubility

Assay Solubility does not affect tablet assay, CU and degradation products. Thus, the risk is low. Content Uniformity

Degradation Products

Dissolution

Memantine HCl exhibits high solubility across the physiological pH range. So Dissolution is unlikely to get affected by solubility of drug substance. Risk is low

Loss on Drying (LOD)

Assay LOD is controlled in the drug substance specification (NMT 0.5%). Thus, it is unlikely to impact assay, CU and dissolution. The risk is low.

Content Uniformity Dissolution

Degradation Products The drug substance is not sensitive to moisture based on forced degradation studies. The risk is low.

Process Impurities

Assay Total impurities are controlled in the drug substance specification (NMT 2.0%). Impurity limits comply with ICH Q3A recommendations. Within this range, process



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Drug Products CQAs

Justification

impurities are unlikely to impact assay, CU and dissolution. The risk is low.


During the excipients compatibility study, no incompatibility between process impurities and commonly used tablet excipients was observed. The risk is low.

Chemical Stability

Assay The drug substance is not exposed to light in solution state during the manufacturing process. Therefore, the risk is low.

Content Uniformity Degradation Products

Dissolution Degradation Products

Flow Properties

Assay

Memantine HCl has poor flow properties. In extreme cases, poor flow may impact assay. The risk is medium.

Content Uniformity

Memantine HCl has very poor flow properties which may lead to poor tablet CU. The risk is high.

Degradation Products The flowability of the drug substance is not related to its degradation pathway or solubility. Therefore, the risk is low.

Dissolution


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Development Strategy and Justification:

Formula and Process Optimization of Immediate Release Tablets:

Development trials of Memantine HCl Hydrochloride Tablets have been carried out with

different combination of excipients to finalize the manufacturing process and specifications.

Each trial was evaluated for feasibility of manufacturing process, physical characteristics and

release profile.

To manufacture Memantine HCl Hydrochloride Tablet 10 mg by direct compression technique.

Table No. 3 Unit formula of batch no MA-01

Ingredients MA-01

mg/tablet

Memantine HCl Hydrochloride 10.00

Microcrystalline Cellulose 195.60

Croscarmellose Sodium 7.80

Silicon dioxide 4.40

Magnesium Stearate 2.20

Total tablet weight 220.00

• Brief Manufacturing Process:

1. Sift Memantine HCl Hydrochloride and half quantity Silicified Microcrystalline

Cellulose.

2. Sift Croscarmellose Sodium and remaining half quantity of Silicified Microcrystalline

Cellulose and Silicon dioxide .

3. Load materials of step no. 1 and step no.2 in blender and blend.

4. Sift Magnesium stearate and add materials of step no. 3 in blender and lubricate.

5. Compress the lubricated blend using suitable tooling.


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To manufacture Memantine HCl Hydrochloride Tablets 10 mg by wet granulation technique.

Table No. 4 Unit formula of batch no MA-02

Ingredients MA-02

mg/tablet

Intra granular

Memantine HCl Hydrochloride 10.00

Microcrystalline Cellulose 194.60


Purified water Qs

Extra granular


Silicon dioxide 4.40

Magnesium Stearate 2.20


Brief Manufacturing Process:

1. Dry mix: Pass the intra granular material i.e. Memantine HCl hydrochloride, Silicified

Microcrystalline Cellulose and Croscarmellose Sodium and mix.

2. Granulation: Granulate the dry mix with purified water, to obtain desired granules.

3. Drying and sifting: Dry the wet mass at 600C till desired LOD (3 - 5 %) is achieved. Sift

the dried granules.

4. Blending: Weigh the quantity of extra granular material, sift (except magnesium stearate)

and blend.

5. Lubrication: Lubricate the above blend with magnesium stearate.

6. Compression: Compress the lubricated blend using suitable tooling.


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To manufacture Memantine Hydrochloride Tablets 10 mg by wet granulation technique by using different binders.

Table No.5 Unit formula of batch no MA-03, MA04, MA05 and MA06.

Sr. No.

Ingredients MA-03 MA-04 MA-05 MA-06 mg/tab mg/tab mg/tab mg/tab

Intra granular

1. Memantine Hydrochloride

10.000 10.000 10.000 10.000

2. Microcrystalline Cellulose 191.60 191.60 192.10 192.40

3. Croscarmellose Sodium 4.400 4.400 4.400 4.400

4.

Low substituted hydroxypropyl cellulose (L-HPC LH-11)

3.00 -- -- --

5. Pregelatinized starch (Lyacatab C) -- 3.00 -- --

6. PVPK 30 -- -- 2.500 --

7. Hypromellose (HPMC E5 Premium LV) -- -- -- 2.200

8. Purified Water qs qs Qs Qs

Extra granular

9. Croscarmellose sodium 4.400 4.400 4.400 4.400

10. Silicon dioxide 4.400 4.400 4.400 4.400

11. Magnesium Stearate 2.200 2.200 2.200 2.200

Core Tablet Weight 220.000 220.000 220.000 220.000

Coating

12.

Opadry white

7.000

7.000

7.000

7.000

13. Purified Water qs qs Qs qs

Coated Tablet Weight 227.000 227.000 227.000 227.000


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Brief Manufacturing Process:

7. Dry mix: Pass the intra granular material i.e. Memantine HCl hydrochloride, Silicified

Microcrystalline Cellulose and Croscarmellose Sodium and mix.

8. Granulation: Granulate the dry mix with purified water, to obtain desired granules.

9. Drying and sifting: Dry the wet mass at 600C till desired LOD (3 - 5 %) is achieved. Sift

the dried granules.

10. Blending: Weigh the quantity of extra granular material, sift (except magnesium stearate)

and blend.

11. Lubrication: Lubricate the above blend with magnesium stearate.

12. Compression: Compress the lubricated blend using suitable tooling.



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FINAL MANUFACTURING FORMULA

Table No.6 Unit formula of batch no MA-07.

Sr. No.

Ingredients MA-07 mg/tab

1. Memantine Hydrochloride

10.000

2. Microcrystalline Cellulose 192.400

3. Croscarmellose Sodium 4.400

4. Hypromellose (HPMC E5 Premium LV) 2.200

5. Purified Water Qs

6. Croscarmellose sodium 4.400

7. Silicon dioxide 4.400

8. Magnesium Stearate 2.200

Core Tablet Weight 220.000

9. Opadry white 7.000

10. Purified Water Qs

Coated Tablet Weight 227.000

Final Manufacturing Process:

I Sifting:

a. Sift Memantine Hydrochloride, Croscarmellose Sodium and approximately half the quantity

of Microcrystalline Cellulose through #40 mesh in a geometrical dilution process using

Mechanical Sifter.

b. Resift the above material through #40 mesh two times.

c. Sift remaining quantity of Microcrystalline Cellulose and above material in geometrical

dilution process through #40 mesh using Mechanical Sifter.


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d. Resift above material through #40 mesh two times.

II Dry Mixing:

a. Charge above material in Rapid Mixer Granulator and mix for 10 minutes with impeller on at

slow speed and chopper off.

III Granulation:

a. Binder solution preparation:

Keep purified water in vessel under stirring and add Hypromellose in the vortex formed,

continue stirring till a clear, lump free solution formed.

b. Add the binder solution to Stage: II, in a thin stream with impeller on at slow speed and

chopper off.

c. After complete addition of binder solution, knead for 1 minute with impeller on at slow speed

and chopper off.

IV Drying:

a. Dry stage: III material in Fluid Bed Dryer at 60°C - 65°C inlet temperature till 3% - 5% loss

on drying is obtained (analyzed by IR moisture analyzer at 105°C).

V Sifting & Milling:

a. Sift the dried materials through #20 mesh.

VI Sifting:

a. Sift the extra granular materials (Croscarmellose sodium & Silicon dioxide ) through #40 mesh.

VII Blending:

a. Load the materials of stage: V & VI in blender and blend for 15 minutes.

VIII Lubrication:

a. Sift Magnesium Stearate through #60 mesh using mechanical sifter.

b. Load the above material in blender containing stage: VII material and lubricate for 5

minutes.


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IX Compression:

a. Compression of Memantine HCl tablets 10 mg

Compress the final lubricated blend into tablets with below parameters:

1 Punch: 12 mm x 5.4 mm caplet shaped normal concaved punch.

2 Description: White to off-white, caplet shaped, biconvex, uncoated tablets.

3 Average weight : 220 mg ± 3%

X Coating:

a. Preparation of Coating Solution:

• Take the Purified water in vessel and keep under the stirrer. While stirring purified water,

slowly disperse Insta Coat Universal White in the vortex formed.

• Avoid formation of lumps. Stir for 45 minutes at slow speed. Filter through #200 mesh

nylon cloth.

b. Coating of Memantine HCl tablets 10 mg:

Coat the tablets using above coating solution to achieve 2.7% - 3.7% weight build up.


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Initial assessment of risk for Formulation Variables

The results of the Initial assessment of risk for formulation variables are presented in Table 07

and the justification for the risk assignment is presented in Table 08.

Table No. 07: Initial assessment of risk for formulation variables

Drug Product

CQA

Formulation Variable

Drug Substance

PSD

Silicified Microcrystalline

Cellulose

Croscarmellose Sodium

Magnesium Stearate

Hypromellose

Assay Medium Low Low Low Low

Content Uniformity

Medium

Low Low Low Low

Dissolution Low Low Medium Medium Medium


Low Low Low Low Low


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Table No. 08: Justification for the Initial assessment of risk for formulation variables.


Drug Products CQAs

Justification

Drug Substance PSD

Assay Memantine Hydrochloride has poor flow properties. In extreme cases poor flow may impact assay. The risk is medium.

Content Uniformity Particle size distribution has a direct impact on drug substance flowability and ultimately on CU. The risk is medium.

Dissolution Memantine Hydrochloride shows high solubility across all pH. Hence risk is low.


Memantine Hydrochloride particle size has no impact on stabilility. The risk is low.

Microcrystalline Cellulose

Assay Since the level of Silicified Microcrystalline Cellulose used as diluent and its impact on flow is minimal, it is unlikely to impact assay and CU. The risk is low.

Content Uniformity

Dissolution Memantine Hydrochloride shows solubility across pH high. Since the risk is low.


Microcrystalline Cellulose is compatible with the Memantine Hydrochloride will not impact drug product degradation, the risk is low.

Croscarmellose Sodium

Assay Since the level of Croscarmellose Sodium used is low and its impact on flow is minimal, it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution

Croscarmellose Sodium levels as a superdisintegrant has impact on disintegration time of tablet there by affect the drug release profile. The risk is medium.


Croscarmellose Sodium is compatible with the Memantine Hydrochloride will not impact drug product degradation, the risk is low.

Magnesium Stearate Level

Assay Magnesium Stearate used as lubricant and process is wet granulation and drug is properly mixed; it is not impact on assay and Content uniformity. The risk is low.

Content Uniformity


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Drug Products CQAs

Justification

Dissolution

Memantine Hydrochloride is a highly soluble molecule and but high level of magnesium stearate level will have impact on dissolution. Hence the risk is medium.


Magnesium stearate is compatible with the Memantine Hydrochloride will not impact drug product degradation, the risk is low.

Hypromellose

Assay Silicon dioxide used as binder and it is not impact on assay and Content uniformity. The risk is low. Content Uniformity

Dissolution

Purified Talc act as binder and may impact disintegration time and likely to impact dissolution. The risk is medium.


Since Microcrystalline cellulose is compatible with drug substance and Microcrystalline cellulose will not impact degradation products, the risk is low

The goal of the formulation development is to select the %Disintegrant ratio intragranular, Binder level, Magnesium Stearate level and to understand on the final formulation whether there is any impact on the drug substance particle size. This study also sought to establish the robustness of the proposed formulation.


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Table No. 09: Design of the 23 DOE to study % Disintegrant ratio intragranular, Bi nder level & Lubricant level as variables in formulation

Levels

Factor: Process Variable -1 0 +1

A %Disintegrant ratio intragranular

25 50 75

B Binder level 1.1 2.2 3.3

C Lubricant level 1.1 2.2 3.3

Responses(R) Acceptance Criteria

R1 Bulk Density 0.35-0.55 gm/cc

R2 Tapped Density 0.45-0.65 gm/cc

R3 Compressibility Index (CI) 15-30

R4 Disintegration time NMT 15 mins

R5 Dissolution (45mins) Not less than 80% (Q) of Labeled amount of Memantine Hydrochloride (C12H21N.HCl)

R5 Hardness (N) 60-120

77 Department of Pharmaceutical sciences JJTU JHUNJHUNU

Chapter V Exprimental methods

Table No. 10 : Formula of Qbd trials of formula optimization Sr. No.

Ingredients

MA-07 MA-08 MA-09 MA-10 MA-11 MA-12 MA-13 MA-14

mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab

Intra granular

1. Memantine Hydrochloride 10 10 10 10 10 10 10 10

2. Microcrystalline Cellulose 190.2 194.6 192.4 192.4 192.4 192.4 194.6 194.6

3. Croscarmellose Sodium 6.6 2.2 6.6 2.2 6.6 2.2 6.6 2.2

7. Hypromellose (HPMC E5 Premium LV) 3.3 3.3 1.1 1.1 3.3 3.3 1.1 1.1

8. Purified Water qs qs qs qs qs qs qs qs

Extr a granular

9. Croscarmellose sodium 2.2 6.6 2.2 6.6 2.2 6.6 2.2 6.6

10. Silicon dioxide 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4

11. Magnesium Stearate 3.3 3.3 3.3 3.3 1.1 1.1 1.1 1.1

Core Tablet Weight 220.000 220.000 220.000 220.000 220.000 220.000 220.000 220.000

Coating

12. InstaCoat Universal White (A05R00013) 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000

13. Purified Water qs qs Qs qs qs qs qs qs

Coated Tablet Weight 227.000 227.000 227.000 227.000 227.000 227.000 227.000 227.000



Manufacturing process development with finalized formula

Initial assessment of risk for manufacturing process for Memantine Hydrochloride 10 mg

A risk assessment of the overall drug product manufacturing process was 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 were identified. For each process step, a risk assessment was conducted to identify potentially high risk process variables which could impact the identified intermediate CQAs and, ultimately, the drug product CQAs. These variables were then investigated in order to better understand the manufacturing process and to develop a control strategy to reduce the risk of a failed batch. This method of identifying process variables for further study is illustrated in following figure and is applied in each process step risk assessment.

Step 1 :

Identify Drug Product CQA’s

Step2 : For each process

step, identify intermediate CQAs

that impact drug product CQAs

Step3 : Identify material attributes

and process parameters that may impact the

intermediate CQAs of the process step

Table No. 11: Initial assessment of risk for manufacturing process for Generic Memantine Hydrochloride Tablets 10 mg

Drug

Product CQAs

Process Steps

Dry mix

Granulation

Pre- lubrication Blending

Lubrication

Compression

Coating

Assay

Medium

Low

Medium

Low

Medium

Low

Content Uniformity

High

Low

Medium

Low

Low

Low

Dissolution

Low

High

Low Medium Medium

Low


Low

Low

Low

Low

Low

Low



Table No. 12: Justification for the Initial assessment of risk for manufacturing process for

Memantine Hydrochloride Tablets 10 mg

Process Steps Drug Product CQAs Justification

Dry Mix Assay INproper mixing of drug with excipients may cause variable blend in uniformity. The risk is medium.

Content Uniformity The PSD and cohesiveness of the drug substance adversely impact its mixing of drug substance which, in turn, affects CU. The risk is high.

Dissolution Dry mixing process variables are unrelated to dissolution of product. The risk is low.

Degradation Products Dry mixing process variables are unrelated to degradation of product. The risk is low.

Granulation Assay Content Uniformity

Granulation is performed to improve mixing of drug and enhance flow. Granulation does not affect the assay and CU. The risk is low.

Dissolution Tablet hardness can impact density and plasticity of the granules, thus may be impacted if compression force is not adjusted to accommodate batch-to-batch variability. The risk is high.

Degradation Products Memantine Hydrochloride is not susceptible to Thermal degradation. Compression is unlikely to impact degradation products; therefore, the risk is low.

Pre lubrication Blending

Assay & Blend Uniformity

The granule uniformity which affects assay and CU is controlled by sifting and milling. This step is to blend the granules is likely to impact assay and CU. The risk is medium.

Dissolution This step is unrelated to dissolution. The risk is low.

Degradation Products Blending is unlikely to impact degradation products; therefore, the risk is low.

Lubrication Assay This step is to blend the granules with small quantities of extra granular lubricant and is unlikely to impact Assay and CU. The risk is low. Content Uniformity

Dissolution Over lubrication can impart hydrophobicity to the



Process Steps Drug Product CQAs Justification

blend which in turn may reduce the drug release rate. The risk is medium.

Degradation Products Lubrication is unlikely to impact degradation products; therefore, the risk is low.

Compression Assay In extreme cases, tablet weight variability can lead to-out of-specification assay results. But the flow property of blend is good, so the weight variability is less which in turn less impact on assay. The risk is medium.

Content Uniformity As blend is already slugged and milled. Already content uniformity during blending and lubrication is confirmed. The risk is Low.

Dissolution Tablet hardness may impact the dissolution. The risk is medium.

Degradation Products Compression is unlikely to impact degradation products; therefore, the risk is low.

Coating Assay This step is unrelated to Assay, CU and Dissolution of tablets. The risk is low.

Content Uniformity

Dissolution

Residual Solvent This step is carried out with aqueous system. The risk is low.

Degradation Products Coating is unlikely to impact degradation products; therefore, the risk is low.

Initial assessment of risk for Dry Mix Process Variables:

The Initial assessment of risk for overall manufacturing process identified the risk of dry

mixing time step to impact uniformity as High. Subsequently, blend uniformity was identified as

an intermediate CQA of the powder blend from the dry mixing step. Process variables that could

potentially impact blend uniformity were identified and their associated risk was evaluated.

Below table presents the initial risk assessment for the dry mixing time in granulation process.



Table No. 13: Initial assessment of risk for Process Variables- Dry mixing time

Dry mixing time

Output Material CQA: Content Uniformity And Blend A ssay

Variables Risk

Assessment

Justification and Initial Strategy

Input Material Attr ibutes Memantine HCl PSD

Medium

A small particle size and a wide PSD may adversely impact blend flowability. In extreme cases, poor flowability may cause an content uniformity failure. The risk is medium.

Excipient Flowability Medium Excipient flowability could impact on content uniformity. The risk is medium.

Excipient Bulk Density

Low Since the excipients used have a comparable density. The risk is low.

Table No. 14: Initial assessment of risk for Dry mixing variables

Process Step: Dry mixing Output Material CQA: Assay and Blend Uniformity (BU)

Process Var iables Risk Assessment Justification Rapid mixer granulator

Low RMG is selected based on availability. This risk is low.

Time for mixing

High

The PSD and cohesiveness of the drug substance adversely impact its mixing of drug substance which, in turn, affects Assay & BU. The risk is high.

Initial assessment of risk for Granulation Process Variables:

The Initial assessment of risk for overall manufacturing process identified the risk of dry mixing

time step to impact uniformity as High. Subsequently, blend uniformity was identified as an

intermediate CQA of the powder blend from the dry mixing step. Process variables that could

potentially impact blend uniformity were identified and their associated risk was evaluated.

Below table presents the initial risk assessment for the dry mixing time in granulation process.



Table No. 15: Initial assessment of risk for Process Variables- Granulation

Granulation

Output Material CQA: Bulk density, Hardness and Dissolution

Variables Risk

Assessment


Input Material Attr ibutes Granulation fluid

Medium

A Granulation fluid may adversely impact blend flowability and Hardness. In extreme cases, poor flowability may not achieve desired hardness. The risk is medium.

Kneading time Medium Kneading time could impact on flowability and Dissolution. The risk is medium.

Table No. 16: Initial assessment of risk for Granulation variables

Process Step: Dry mixing Process Var iables Risk Assessment Justification

Bulk density

Medium Granules PSD adversely impact its flow, The risk is medium

Dissolution

High

Granulation fluid can adversely impact its mixing of drug substance which, in turn, affects Assay & CU. The risk is high.

Disintegration Time

Medium Hard granules may impact on disintegration time. The risk is medium.

Hardness

Medium

Granulation fluid and Kneading time can adversely impct on strength of granules so desired hardness will not achieve. The risk is medium.



Table No. 17: Design of the 22 DOE to study Granulation fluid & Kneading time as variables in formulation

Levels

Factor: Process Variable -1 0 +1

A Granulation fluid % (mg/ tab) 12 15 18

B Kneading time (min) 1 3 5

Responses(R) Acceptance Criteria

R2 Bulk Density (gm/cc) 0.66-0.70 gm/cc

R3 Hardness (N) 60-120

R4 Dissolution (45mins) Not less than 80% (Q) of Labeled amount of Memantine Hydrochloride (C12H21N.HCl)

R5 Disintegration time (min) NMT 15 mins



Prelubrication & lubrication Blending

Initial assessment of risk for Prelubrication & Lubrication blending Process Variables

The Initial assessment of risk for Prelubrication and lubrication step to impact CU is medium. Table No. 18 presents the Initial assessment of risk for Prelubrication and Lubrication blending step.

Table No. 18: Initial Risk Assessment of Prelubrication and Lubrication Process

Process step: Prelubrication & Lubrication Blending

Output Material CQA: Content Uniformity (CU)

Variables Risk

Assessment


Input Material Attr ibutes Granule Uniformity

Medium The granules uniformity will have impact on blend Uniformity, hence the risk is medium.

Granule Flowability

Medium The granules flowability will have impact on blend Uniformity, hence the risk is medium.

Granule Bulk Density

Low The granule bulk density has little impact on tablet blend uniformity. The risk is low.

Process Var iables Blender Type

Low

Different blender types have different mixing dynamics. Mixing machanism is selected based on the blender type availability. The risk is low. However, if the blender type is changed during scale-up or commercialization, the risk should be re-evaluated.

Blending Time

Medium

Under or over - mixing in blender with fixed speed for insufficient time will result in suboptimal BU. The risk is medium.

1. Tablet Compression Process Development

Initial assessment of risk for Tablet Compression Process Variables

Based on the Initial assessment of risk for overall manufacturing process, the risk of the

compression step to impact Uniformity of Dosage Units and Drug Release 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 assessment of

risk for compression process variables are summarized below.



Table No. 19: Initial Risk Assessment of Compression Process

Process step: Compression

Output Material CQA: Uniformity of Dosage Units by CU and Drug Release

Variables

CQAs Risk

Assessment


Input Material Var iables

Blend Assay Uniformity of Dosage Units

Low The blend assay is acceptable within the range of 95 to 105%. This low variability is unlikely to impact UOD and Drug Release. The risk is low.

Drug Release

Low

Blend Uniformity Uniformity of Dosage Units

Low The lubricated blend demonstrated acceptable BU (% RSD < 5%) during the lubrication process . Therefore, the risk is low. Drug Release Low

Blend Flowability

Uniformity of Dosage Units

Low

Blend flowability could impact powder flow from the hopper to the feed frame and ultimately to the die cavity. However, adequately flow was achieved after wet granulation. The addition of extragranular lubricants also improve blend flowability. The risk is low.

Drug Release

Low

Blend Bulk Density


Low The blend bulk density is consistently 0.68gm/ml and has little impact on CU and Drug Release. The risk is low. Drug Release Low

Process step: Compression Output Material CQA: Uniformity of Dosage Units by CU and Drug Release

Variables

CQAs Risk

Assessment


Process Variables: Compression Force Press Type and

Number of Stations


Low The press type was selected based onequipment availability and it will not affect the UOD and dissolution. So Risk is low. Drug Release Low

Tooling Design Uniformity of Dosage Units

Low Tooling design was selected based upon the size and shape of the Reference Product and it is fixed for this product, hence tooling design does not impact the UOD and Drug Release.

Drug Release Low Tablet Hardness Uniformity of

Dosage Units Low The tablet hardness would not impact the

UOD, the risk is low. Drug Release High Drug release will be impacted by tablet

hardness, hence risk is high. Press Speed

(Dwell Time) Uniformity of Dosage Units

Medium A faster than optimal press speed may cause inconsistent die filling and weight variation which may then impact UOD, hence risk is



Process step: Compression

Output Material CQA: Uniformity of Dosage Units by CU and Drug Release

Variables

CQAs Risk

Assessment


medium.

Drug Release Low Drug release may not be getting impacted by the tablet press speed, hence risk is low.

Table No. 20: Risk assessment of the Compression variables

Process Step: Tablet Compression Drug Product CQAs: Par ticle Size Distr ibution, Dissolution and Uniformity of Dosage Units Pre-compression force

Particle Size Distribution

Low

Particle Size distribution is unrelated to pre-compression force it will mainly depends on main compression force. The risk is low.

Dissolution

Low

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 at optimum based on experience with similar formulations compressed on the same equipment. Adjustment may be needed. The risk is medium.


Low

Pre-compression force will not effect Granules Flowability. The risk is Low.

Main compression force


High Main Compression force will effect Dissolution.

Dissolution Medium Uniformity of Dosage Units

Low



Process Step: Tablet Compression Drug Product CQAs: Par ticle Size Distr ibution, Dissolution and Uniformity of Dosage Units Hopper design and vibration


Low Granules flow properties are satisfactory, the risk of segregation is minimized. Tablet press vibrations and the hopper angle design are unlikely to have an impact on CU and dissolution. The risk is low.

Dissolution Low


Low

Hopper fill level Particle Size Distribution

Low The blend has acceptable flowability and the hopper fill level is maintained at 50%. Maintaining the hopper fill level makes it improbable that this parameter will impact Particle size distribution and dissolution. The risk is low.

Dissolution Low


Low

Compression run time


Medium

It is possible during long compression run times that the 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.


Low

The following experiments were undertaken to investigate the relationship between the input

material attributes and process parameters related to compression and the final drug product

quality attributes.

Effect of Main Compression Force, Press Speed and Tablet Hardness

Compression force can affect numerous quality attributes including hardness, disintegration, dissolution, weight variability and appearance. The Hardness may also impact the compressibility and compactability of the granules which would then impact final tablet hardness and dissolution.

Compression was carried out using 16 Station, compression machine. The tablet press run at Low and High speed to check uniformity of weight and Hardness adjusted at Low and High Hardness to check impact on drug release.



Tablet Coating Process Development

Initial assessment of risk for Tablet Coating Process Variables

Based on the Initial assessment of risk for overall manufacturing process, the risk of the coating step to impact Degradation Product was identified as medium because of exposure to temperature during coating process. Process variables that may impact these drug product CQAs were identified and their associated risk was evaluated. The results of the Initial assessment of risk for coating process variables are summarized in table.

Table No. 21: Initial assessment of risk for Coating Process Variables

Process step: Coating Process Output Material CQA: Physical Parameters, Dissolution

Variables Risk Assessment Justification and Initial Strategy Input Material Variables

Uniformity of Weight

Low

The lubricated blend properties as well as compression parameters are optimized, so that no weight variation problem was observed, however uniformity of weight does not impact degradation product. Hence risk is low.

Tablet Hardness and Friability

Low

The lubricated blend properties as well as compression parameters are optimized, so that tablet parameters are observed with no hardness variations and friability having less than 1.0%, however tablet hardness and friability does not impact degradation product. Hence risk is low.

Pan Load

Low

Pan load may not impact the degradation product, however optimum load is taken to avoid common coating issues like physical appearance. The risk is low.

Product Bed Temperature

Low

Product bed temperature may impact the degradation product due to exposure to heat during coating; however risk is medium for degradation product.

Coating was carried out in conventional coater coating pan. The bed temperature observed between 40°C to 50°C, pan RPM sets at 3- 5 RPM, spray pump RPM set from 2-5 RPM and

Atomization air pressure observed at about 1.2- 1.5 Kg/cm2 . The CQA’s observed after coating and results are summarized as below.



STABILITY STUDY

The stability study was carried out Accelerated condition 40°C/75% RH for formulation F16 up to

3 month. At every 30 days time interval, the tablets were analyzed for drug content uniformity

and In-vitro drug release.



Executive Summary Memantine HCl ODT

Initially, the quality target product profile (QTPP) was defined based on the properties of

the drug substance. Identification of critical quality attributes (CQAs) was based on the severity

of harm to a patient (safety and efficacy) resulting from failure to meet that attributes of quality

for drug product. Our investigation during pharmaceutical development focused on those CQAs

that could be impacted by a realistic change to the drug product formulation or manufacturing

process. For generic Memantine HCl ODT, these CQAs included Assay, Content Uniformity,

Dissolution, Degradation Products and Residual Solvents.

Risk assessment was used throughout development to identify potentially high risk

formulation and process variables and to determine which studies were necessary to achieve

product and process understanding in order to develop a control strategy. Each risk assessment

was then updated after development to capture the reduced level of risk based on our improved

product and process understanding. For formulation development, aqueous wet granulation was

selected over direct compression and dry granulation method. Excipient selection was based on

the Reference Product Composition, IIG limits and Drug-excipient compatibility studies.

Formulation development) was conducted in two stages. First is formulation optimisation

and second is process optimisation. The High Performance Liquid Chromatography (HPLC)

method was validated and implemented to monitor blend uniformity and to reduce the risk

associated with the Pre granulation blending, blending and lubrication steps.

Finally, we proposed a control strategy that includes the material attributes and process

parameters identified as potentially high risk variables during the initial risk assessments. Our

control strategy also includes in-process controls and finished product specifications. The

process will be monitored during the lifecycle of the product and additional knowledge gained

will be utilized to make adjustments to the control strategy as appropriate.



Quality Target Product Profile for the test Product

Based on the clinical and pharmacokinetic (PK) characteristics a quality target product profile

(QTPP) was defined and justified for Memantine HCl ODT 10 mg (refer Table No. 22). Table No. 22: Quality Target Product Profile (QTPP) for Memantine HCl ODT 10 mg

QTPP Elements Target Justification Dosage form Tablet Pharmaceutical equivalence

requirement: same dosage form

Dosage design Orally Disintegrating Tablets Orally Disintegrating Tablets needed to meet label claims

Route of administration Oral Pharmaceutical equivalence requirement: same route of administration

Dosage strength 10 mg Pharmaceutical equivalence requirement

Stability At least 24-month shelf-life at room temperature

Better Product shelf-life

Table No. 23: Target Product Profile (QTPP) for Memantine HCl ODT 10 mg

TPP Elements Target Justification

Drug product quality

attributes

Physical Attributes

Pharmaceutical equivalence requirement: Meeting the same compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality).

Identification Assay Content Uniformity Dissolution Degradation Products Residual Solvents Loss on drying Microbial Limits

Container closure system Suitable container closure system to achieve the target shelf-life and to ensure tablet

HDPE bottles and Child Resistant (CR) Caps are selected for the stability of the



TPP Elements Target Justification integrity during shipping. drug product. Administration/Concurrence with labelling

The tablets can be administered with or without food

Information is provided in the Reference Product label.

Alternative methods of administration

None None are listed in the Reference Product label.

Table No. 24 summarizes the quality attributes of generic Memantine HCl ODT and

indicates which attributes were classified as drug product critical quality attributes (CQAs). For

this product, assay, content uniformity (CU), dissolution study, residual solvent and degradation

products are investigated and discussed in detail in subsequent formulation and process

development studies.

On the other hand, CQAs including identification, loss on drying 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 a good pharmaceutical quality system and the control strategy

Table No. 24: Critical Quality Attributes (CQAs) of Memantine HCl ODT 10 mg

Attributes of quality for drug product

Target Is this

a CQA?

Justification

Physical Attributes

Appearance

Colour and shape acceptable to the patient. No visual tablet defects observed.

No

Colour, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical. The targetis set to ensure patient acceptability.

Size

Similar to Reference Product

No

For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet dimensions is set similar to the Reference Product.

Score configuration

Unscored

No

The Reference Product is an unscored tablet; therefore, the generic tablet will be unscored.




Target Is this

a CQA?

Justification

Friability NMT 1.0% w/w No Friability is a routine test per compendial requirements for tablets. A target of NMT 1.0% w/w of mean weight loss assures a low impact on patient safety and efficacy and minimizes customer complaints

Identification

Positive for Memantine HCl

Yes*

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% w/w 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 Uniformity (CU)

Conforms to USP <905> Uniformity of Dosage Units

Yes

Variability in content uniformity will affect safety and efficacy. Both formulation and process variables impact content uniformity, so this CQA will be evaluated.

Dissolution

Not less than 80% (Q) of the labeled amount of memantine is dissolved in 15 minutes.

Yes

Failure to meet the dissolution specification can impact bioavailability. Both formulation and process variables affect the Dissolution. This CQA will be investigated throughout formulation and process development.




Target Is this

a CQA?

Justification

Loss on drying (w/w, at 105°C for 3 hours)

NMT 8 % 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, is not sensitive to hydrolysis and non hygroscopic. So moisture will not impact stability.

Residual Solvents USP <467> option 1

Yes* 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 unlikely to impact this CQA.

Formulation and process variables are unlikely to impact the CQA. Therefore, the CQA will not

be investigated and discussed in detail in subsequent risk assessment and pharmaceutical

development. However, the CQA remains a target element of the drug product profile and should

be addressed accordingly.

Chemical Properties

Chemical stability in solid state and in solution:

Stress testing (forced degradation) was carried out by DMF holder on of Memantine HCl

to study its impurity profile, degradation pathway and to facilitate the development of a stability-

indicating method. In addition, knowledge obtained from the forced degradation studies was

used during formulation and process design and development to prevent impurities generation.

The stressed samples were compared to the unstressed sample (control).

Biological Properties

Biopharmaceutical Classification:

Based on the available literature (Reference Clinical Pharmacology & Biopharmaceutics)

and pH solubility studies across the different pH, the Memantine HCl shows high solubility.



Hence, Memantine HCl is considered as highly soluble drug and completely absorbed following

oral administration. So, it may be considered as BCS Class I.

Assessment of Risk FOR Drug Substance Attributes

A assessment of risk for 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 high, medium or low. 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. For each risk

assessment performed, the rational for the risk basement tool selection and the details of the risk

identification, analysis and evaluation are available to the FDA reviewer on request. The same

relative risk ranking system was used throughout pharmaceutical development and is

summarized in Table No 25.

Table No. 25: 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 physicochemical and biological properties of the drug substance, the initial risk

assessment of drug substance attributes on drug product CQAs is shown in Table No 26.



Table No. 26: Initial risk assessment of risk for drug substance attributes

Drug Product CQAs

Drug Substance Attr ibutes

Solid State Form

Particle Size

Distrib ution (PSD)

Hygrosco picity

Solubi

lity

Loss on

Dryi ng

Resid ual

Solven ts

Process Impuri

ties

Chemi cal

Stabili ty

Flow Propert

ies

Assay

Low

Medium

Low

Low

Low

Low

Low

Low

Medium

Content Uniformity

Low

Medium

Low

Low

Low

Low

Low

Low

High

Dissolution

Low

Low

Low

Low

Low

Low

Low

Low Low

Degradatio n Products

Low

Low

Low

Low

Low

Low

Low

Low

Low

The justification for the assigned level of risk is provided in Table No. 27

Table No. 27: Justification for the Initial assessment of risk for drug substance attributes


Drug Products CQAs

Justification

Solid State Form

Assay Drug substance solid state form does not affect tablet assay and CU. The risk is low Content Uniformity

Dissolution Memantine HCl is highly soluble compound; therefore, it does not affect Dissolution. The risk is low.


Force degradation data and crystalline form of the drug substance represents that Memantine HCl is a stable molecule. The risk is low.

Particle Size Distribution (PSD)

Assay


Content Uniformity Particle size distribution has a direct impact on drug substance flowability and ultimately impact on CU. Due




Drug Products CQAs

Justification

to the fact that the manufacturing process is a wet granulation method, hence risk is considered as medium.

Dissolution Memantine HCl is highly soluble compound; therefore, it does not affect Dissolution. The risk is Low.

Degradation Products The representative PSD of drug substance is stable, hence the risk is low.

Hygroscopicity

Assay Memantine HCl is non-hygroscopic. The risk is low.

Content Uniformity Dissolution Degradation Products

Solubility

Assay Solubility does not affect tablet assay, CU and degradation products. Thus, the risk is low. Content Uniformity


Dissolution

Memantine HCl exhibits high solubility across the physiological pH range. So Dissolution is unlikely to get affected by solubility of drug substance. Risk is low

Loss on Drying (LOD)

Assay LOD is controlled in the drug substance specification (NMT 0.5%). Thus, it is unlikely to impact assay, CU and dissolution. The risk is low.


Degradation Products The drug substance is not sensitive to moisture based on forced degradation studies. The risk is low.

Process Impurities

Assay Total impurities are controlled in the drug substance specification (NMT 2.0%). Impurity limits comply with ICH Q3A recommendations. Within this range, process impurities are unlikely to impact assay, CU and dissolution. The risk is low.

Content Uniformity

Dissolution


During the excipients compatibility study, no incompatibility between process impurities and commonly used tablet excipients was observed. The risk is low.

Chemical Stability

Assay The drug substance is not exposed to light in solution state during the manufacturing process. Therefore, the risk is low.

Content Uniformity Degradation Products

Dissolution





Drug Products CQAs

Justification

Flow Properties

Assay

Memantine HCl has poor flow properties. In extreme cases, poor flow may impact assay. The risk is medium.

Content Uniformity

Memantine HCl has very poor flow properties which may lead to poor tablet CU. The risk is high.


The flowability of the drug substance is not related to its degradation pathway or solubility. Therefore, the risk is low.

Excipients:

The excipients used in Memantine HCl ODT were selected based on the excipients used in the

other ODT Product. A summary of the drug-excipients compatibility studies and the selection of

each excipient grade are provided in the following section.

Drug - Excipient Compatibility Studies

The excipients compatibility was assessed through HPLC analysis of binary mixtures of

excipient and drug substance i.e., Memantine HCl at different ratio in the solid state. Samples

were stored at 40°C/75% RH for up to 4 weeks. Diluent, Binder, Disintegrant, Sweetener,

Flavour, lubricant and Glidant were evaluated in the excipient compatibility study.

Excipient Grade Selection

Based on the results of drug-excipients compatibility studies, identical excipient types to the

Reference Product formulation, based on the allowable amount in IIG database were selected for

the generic product development. The selection of excipient grade and supplier was based on

literature knowledge about excipients and consistent quality supplies of supplier which are

mentioned in Table No. 28 The level of excipients used in the formulation was studied in

subsequent formulation development studies.



Table No. 28: Excipients Grade Selection

Sr . N o.

Material Name

Brand Name/

Grade

Category

Supplier

IIG

Route of

Administrati on

1

Mannitol

Pearlitol 160C

Diluent

Roquette

454.20

Oral; Tablets

2

Microcrystalline cellulose

Avicel PH 101

Diluent

FMC Bio Polymer

232.74

Oral; Tablets

3

Pregelatinized starch

Lycatab C

Disintegran t

Roquette

345.95

Oral; Tablets

4

Glycine

Glycine Disintegran

t Finar

Chemical

163.31

Oral; Tablets

5

Microcrystalline cellulose

Avicel PH 102

Diluents

FMC Bio Polymer

231

Oral; Tablets

6 Crospovidone Polyplasdone XL 10

Disintegran t

ISP Chemical

300.00 Oral; Tablets

7

Aspartame

Aspartame

Sweetener Nutraswe

et company

20.00

Oral; Tablets

8

Peppermint Flavour 501500TP0504

Peppermint Flavour

501500TP050 4

Flavour

Firmenich

11.00

Oral; Tablets

9 Silicon dioxide

Syloid 244 FP

Glidant

Grace

99 Oral; Tablets

10 Magnesium stearate Magnesium stearate

Lubricant

Ferro

400.748 Oral; Tablets

Mannitol and Microcrystalline cellulose comprise about 64 % of the total drug product

composition. Mannitol and Microcrystalline cellulose are among the commonly used fillers for

wet granulation formulations, both individually and in combination with each other, because they

exhibit appropriate flow and compression properties.



Drug Product

Formulation Development

Initial assessment of risk for Formulation Variables

The results of the Initial assessment of risk for formulation variables are presented in Table No. 29 and the justification for the risk assignment is presented in Table No. 30.

Table No. 29: Initial assessment of risk for formulation variables

Drug Produc

t CQA

Formulation Variable Drug Substa nce PSD

Mannit ol /Microc rystallin e cellulose (PH 101) ratio

Preg elati nize d starc h

Gly cine

Microc rystalli ne cellulos e (PH 102)

Crosp ovido ne

Asp arta me

Peppe rmint Flavou r 50150 0TP05 04

Sili con dio xid e

Mag nesi um stear ate

Assay

Mediu m

Low Low Low Low Low Low Low Lo w

Low

Content Unifor mity

Mediu m

Low Low Low Low Low Low Low Lo w

Low

Dissolu tion

Mediu m

Medium Medi um

Med ium

Mediu m

Mediu m

Low Low Me diu m

Medi um

Degrad ation Product s

Low Low Low Low Low Low Low Low Lo w

Low



Table No. 30: Justification for the Initial assessment of risk for formulation variables


Drug Products CQAs

Justification

Drug Substance PSD

Assay


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, the risk is high

Dissolution

The drug substance is highly soluble compound; therefore, PSD can not affect dissolution. The risk is low


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.

Mannitol/ MCC Ratio

Assay Mannitol/ MCC ratio can impact the flow properties of the blend. This, in turn, can impact tablet CU and assay. As the manufacturing process is wet granulation, the risk is low.

Content Uniformity

Dissolution Mannitol/ MCC ratio can impact dissolution via tablet disintegration pattern. The risk is High.


Since both Mannitol and MCC are compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Pregelatinized starch

Assay Pregelatinized starch is a hydrophilic binder; it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution

Pregelatinized starch level can impact binding of Memantine HCl in blend and disintegration time which in turn impact dissolution of the tablet. The risk is low


Pregelatinized starch is compatible with the Memantine HClwill not impact drug product degradation, the risk is low.

Glycine

Assay Glycine acts as disintegrant, it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution Glycine level can impact disintegration time which in turn impact dissolution of the tablet. The risk is low

Degradation Glycine is compatible with the Memantine HCl will not




Drug Products CQAs

Justification

Drug Substance PSD

Assay


Content Uniformity


Dissolution




Products impact drug product degradation, the risk is low. Crospovidone

Assay Crospovidone acts as disintegrant, it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution

Crospovidone level can impact disintegration time which in turn impact dissolution of the tablet. The risk is low


Crospovidone is compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Peppermint Flavour

Assay The level of Peppermint Flavour used is low and it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution Peppermint Flavour level do not impact disintegration time and dissolution of the tablet. The risk is low.


Peppermint Flavour is compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Aspartame

Assay The level of Aspartame used is low and it is unlikely to impact assay and CU. The risk is low. Content Uniformity

Dissolution Aspartame level do not impact disintegration time and dissolution of the tablet. The risk is low.


Aspartame is compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Silicon dioxide

Assay The level of Silicon dioxide used is low and it is unlikely

to impact assay and CU. The risk is low. Content Uniformity




Drug Products CQAs

Justification

Drug Substance PSD

Assay


Content Uniformity


Dissolution




Dissolution Silicon dioxide level do not have impact on dissolution of the tablet. The risk is high.


Silicon dioxide is compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Magnesium Stearate Level

Assay

The level of magnesium stearate used is low and it is

unlikely to impact assay and CU. The risk is low.

Content Uniformity

Dissolution

Magnesium stearate level can impact disintegration time which in turn impact dissolution of the tablet. The risk is high.


Magnesium stearate is compatible with the Memantine HCl will not impact drug product degradation, the risk is low.

Drug Substance Particle Size Selection for Product Development

Since the Memantine HCl is highly soluble drug substance, hence there is no impact

of particle size on the drug substance solubility and/ or dissolution in the product.

Process Selection

As Memantine HCl displays poor flowability as evidenced by the Compressibility

Index, Hausner Ratio. Poor material flow may produce tablets with high weight and content

variability due to an uneven distribution of the drug substance in the blend and eventually,

uneven filling of die cavities on the tablet press. Hence uniform distribution of the



Memantine HClin the tablet dosage form is critical.

Direct compression of the blend was performed. The lubricated blend shows poor flow

properties and, during compression tabletting properties such as weight varriation was observed.

Therefore, Direct compression was considered an unacceptable process for this formulation.

Wet granulation exhibits acceptable blend properties (i.e. flow, content uniformity etc) and good tabletting properties (i.e. appearance, weight variation, hardness etc). So wet granulation with water is selected for further drug product development efforts.

Formulation Development Study

Development Strategy – Memantine HCl ODT is available in strength 10 mg. From the

Formulation development focused on evaluation of the high risk formulation variables as

identified in the initial risk assessment shown in Table 29. The development was conducted in

2 studies.

Formulation Development Study 1#: The first formulation study was conducted to evaluate the

impact of the following on the drug product CQAs i.e.

� Optimization of Pre gelatinized starch (binder) Concentration

� Optimization of Glycine (Disintegrant) Concentration

� Optimization of Mannitol/ Microcrystalline cellulose (diluents) ratio.

Formulation Development Study 2#: The second formulation study was conducted to evaluate

levels of extra granular lubricant on the drug product CQAs.

� Optimization of Crospovidone Polyploasdone XL10” (Disintegrant) Concentration

� Optimization of Aspartame Concentration.

� Optimization of Peppermint Concentration

� Optimization of Magnesium Stearate (Lubricant) Concentration

� Optimization of Silicon dioxide concentration.

Formulation development studies were conducted at laboratory scale. Table No. 31 details the equipment and the associated process parameters used in these studies.



Table No. 31 Equipment and fixed process parameters used in formulation development studies

Process Step Equipment Sifting of Intragranular materials

Sieve - # 40 mesh

Dry mix • RMG Granulation and Drying

• RMG

Sifting and Milling • Sieve : # 30 mesh • Multi mill screen : 1.5 mm and 1.0 mm

Blending

• Sieve : # 40 mesh • Blender : Double Cone Blender

• Speed : 16 ± 1 rpm • Time : 15 minutes

Lubrication

• Sieve : # 60 mesh • Blender : Double Cone Blender • Speed : 16 ± 1 rpm

• Time : 3minutes Tablet Compression

Strength 10 mg Equipment Cad mach 16 stations

Tooling 8 .5 mm round shape plain.

Appearance White to off white, round, tablets, Target Tablet Wight

200 mg

DT Not more than 60 sec

Friability Not more than 1.0 %



Formulation Development:

Formulation Development Study 1#:

Optimization of Pregelatinized starch (binder) level in the Formulation

Table No. 32: Unit formula of batch no. ME-01, ME-02, ME-03.

Sr. No.

Name of Ingredients

ME-01

ME-02

ME-03

Intragranular Mg /Tablet

1 Memantine HCl* 14.53 14.53 14.53

2 Mannitol 60 (Pearlitol 160C) 92.97 92.97 92.97

3 Microcrystalline cellulose (Avicel PH 101) **

35.00

38.00

32.00

4 Pregelatinized starch (Lycatab C) 20.00 17.00 23.00

5 Glycine USP 4.00 4.00 4.00

6 Purified Water # q. s. q. s. q. s.

Extr agranular

7 Microcrystalline cellulose PH 102

5.50 5.50 5.50

8 Crospovidone (Polyplasdone XL 10)

10.00 10.00 10.00

9 Aspartame

5.00 5.00 5.00

10 Peppermint Flavour 501500TP0504

1.00 1.00 1.00

11 Silicon dioxide (Syloid 244 FP) 6.00 6.00 6.00

Lubrication

12 Magnesium stearate 6.00 6.00 6.00

Total weight of Tablets (core) 200.000 200.00 200.00

* Any Increase in the quantity of Memantine HCl should be adjusted with Microcrystalline

Cellulose (Avicel PH 101).



** Standard quantity is based on the 100% Assay on as is basis as Memantine HCl

. # Does not contribute to the final weight of the tablets.

Manufacturing Procedure:

1. sifting and dry mix:

Co-sift Memantine HCl , Mannitol 60 (Pearlitol 160C), Microcrystalline Cellulose (Avicel PH

101), Pregelatinized starch (Lycatab C) & Glycine through #40 mesh. Transfer above sifted

material into the RMG and Dry mix for 20 minutes.

2. Granulation:

Add the granulating fluid in the material of step 1 and proceed for granulation.

3. Drying:

Dry the granules in the dryer till required loss on drying 1.0 to 2.5 %w/w is achieved (at 105°C,

for 5 min).

4. Sizing and Milling: Sift the dried material of step 3 through #30 mesh.

5. Blending:

Co-Sift Microcrystalline cellulose (Avicel pH 102), Crospovidone (Polyplasdone XL 10), Silicon

dioxide (Syloid 244 FP), Aspartame and Peppermint Flavour 501500TP0504 through #40 mesh

and blended with step 4 for 15 mins.

6. Lubrication:

Sift Magnesium stearate through # 60 mesh and transfer it to the step 5 and blend for 4 minutes.

7. Compression:

Compress the lubricated blend using 8.50 mm, round shape.



Optimization of Glycine USP (Disintegration) level in the Formulation


Sr. No.

Name of Ingredients

ME-04

ME-05

ME-06


1 Memantine HCl* 14.53 14.53 14.56

2 Mannitol 60(Pearlitol 160C) 92.97 92.97 92.97


35.00

37.00

33.00


5 Glycine USP 4.00 2.00 6.00

6 Purified Water # qs q.s. q.s.

Extra granular


5.50 5.50 5.50


10.00 10.00 10.00

9 Aspartame

5.00 5.00 5.00


1.00 1.00 1.00

11 Silicon dioxide (Syloid 244 FP)

6.00 6.00 6.00

Lubrication

12 Magnesium stearate 6.00 6.00 6.00 Total weight of Tablets (core) 200.000 200.00 200.00



** Standard quantity is based on the 100% Assay on as is basis as Memantine HCl.

# Does not contribute to the final weight of the tablets.




1. sifting and dry mix:

Co-sift Memantine HCl, Mannitol 60(Pearlitol 160C), Microcrystalline Cellulose (Avicel PH


material into the RMG and dry mix for 20 minutes.

2. Granulation:

Add the granulating fluid in the material of step 1 and proceed for granulation.

3. Drying:

Dry the granules in the Fluid bed processor till required loss on drying 1.0 to 2.5 %w/w is

achieved (at 105°C, for 5 min).

4. Sizing and Milling: Sift the dried material of step 3 through #30 mesh.

5. Blending:




6. Lubrication:


7. Compression:




To study the impact of interchange of diluents in the Formulation

Table No. 34: Unit formula of batch no. ME-07, ME-08.

Sr. No. Name of Ingredients ME-07 ME-08

Intragranular

1 Memantine HCl* 14.53 14.53

2 Mannitol 60(Pearlitol 160C) 92.97 35.00


35.00

92.97

4 Pregelatinized starch (Lycatab C) 20.00 20.00

5 Glycine USP 4.00 4.00

6 Purified Water # qs q.s.


5.50 5.50


10.00 10

9 Aspartame

5.00 5.00


1.00 1.00


6.00 6.00

12 Magnesium stearate 6.00 6.00

Total weight of Tablets (core) 200.000 200.00



** Standard quantity is based on the 100% Assay on as is basis as Memantine HClUSP.





1.sifting and dry mix:




2. Granulation:

Add the granulating fluid in the material of step 1 and proceed for

3. Drying:



4. Sizing and Milling:

Sift the dried material of step 3 through #30 mesh.

5. Blending:




6. Lubrication:


7. Compression:




Formulation Development Study 2 #:

Optimization of Crospovidone Polyplasdone XL 10 Disintegration level in the Formulation


Sr. No. Name of Ingredients ME-09 ME-10 ME-11


1 Memantine HCl* 14.53 14.53 14.53



35.00

39.00

31.00


5 Glycine USP 4.00 4.00 4.00


Extragranular


5.50 5.50 5.50


10.00 6.00 14.00

9 Aspartame

5.00 5.00 5.00


5.00 1.00 1.00


1.00 6.00 6.00

Lubrication













2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Optimization of Aspartame level (Sweetner) in the Formulation

Table No. 36: Unit formula of batch no. ME-12, ME-13, ME-14

Sr. No.

Name of Ingredients

ME-12

ME-13

ME-14


1 Memantine HCl* 14.53

14.53

14.53

2 Mannitol 60(Pearlitol 160C) 92.97

92.97

92.97


35.00

37.00

33.00 4 Pregelatinized starch (Lycatab C)

20.00

20.00

20.00 5 Glycine USP

4.00

4.00

4.00 6 Purified Water #

qs

q.s.

q.s. Extragranular


5.50

5.50

5.50


10.00

10.00

10.00

9 Aspartame

5.00

3.00

7.00


1.00

1.00

1.00


6.00

6.00

6.00

Lubrication













2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Optimization of Peppermint (Flavour) level in the Formulation




1 Memantine HCl* 14.53 14.53 14.53

2 Mannitol 60(Pearlitol 160C)

92.97

92.97

92.97

3 Microcrystalline cellulose (Avicel PH 101) * 35.00

35.25

34.75

4 Pregelatinized starch (Lycatab C)

20.00

20.00

20.00 5 Glycine USP 4.00 4.00 4.00

6 Purified Water #

qs

q.s.

q.s. Extragranular

7

Microcrystalline cellulose PH 102

5.50

5.50

5.50 8 Crospovidone (Polyplasdone XL 10) 10.00 10.00 10.00 9 Aspartame 5.00 5.00 5.00

10


1.00

0.75

1.25

11

Silicon dioxide (Syloid 244 FP)

6.00

6.00

6.00 Lubrication

12 Magnesium stearate 6.00 6.00 6.00

Total weight of Tablets (core) 200.000 200.00 200.00












2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Optimization of Magnesium Stearate (lubricant) level in the Formulation




1 Memantine HCl* 14.53 14.53 14.53



35.00

36.00

34.00


5 Glycine USP 4.00 4.00 4.00


Extragranular


5.50

5.50

5.50


10.00

10.00

10.00

9 Aspartame

5.00

5.00

5.00


1.00

1.00

1.00


6.00

6.00

6.00

Lubrication













2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Optimization of Silicon dioxide (Glidant) level in the Formulation


Sr. No.

Name of Ingredients

ME-21

ME-22

ME-23


1 Memantine HCl * 14.53

14.53

14.53

2 Mannitol 60(Pearlitol 160C) 92.97

92.97

92.97


35.00

36.00

34.00

4 Pregelatinized starch (Lycatab C) 20.00

20.00

20.00

5 Glycine USP 4.00

4.00

4.00

6 Purified Water # qs

q.s.

q.s.

Extr agranular 7

Microcrystalline cellulose PH 102

5.50

5.50

5.50 8

Crospovidone (Polyplasdone XL 10)

10.00

10.00

10.00 9

Aspartame

5.00

5.00

5.00 10


1.00

1.00

1.00 11

Silicon dioxide (Syloid 244 FP)

6.00

5.00

7.00 Lubr ication













2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Table No. 40: Final Unit formula reproducible of batch no. ME-24.

Sr.No Strength 10 mg B. No. ME-24

Intra Granular mg/tab 1. Memantine HClUSP * 14.530 2. Mannitol 60(Pearlitol 160C) 92.970 3. Microcrystalline cellulose (Avicel PH 101) 35.000 4. Pregelatinized starch (Lycatab C) 20.000 5. Glycine 4.000 6. Purified Water # q.s

7. Microcrystalline cellulose (Avicel PH 102)

5.500

8. Crospovidone (Polyplasdone XL 10)

10.000

9. Aspartame 5.000 10. Peppermint Flavour 501500TP0504 1.000

11. Silicon dioxide

(Syloid 244 FP) 6.000

12. Magnesium stearate 6.000 Tablet Weight (mg) 200.000












2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Initial assessment of risk for Drug Product Manufacturing Process

A risk assessment of the overall drug product manufacturing process was 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 were identified. For each process step, a risk assessment was conducted to

identify potentially high risk process variables which could impact the identified intermediate

CQAs and, ultimately, the drug product CQAs. These variables were then investigated in order

to better understand the manufacturing process and to develop a control strategy to reduce the

risk of a failed batch. This method of identifying process variables for further study is illustrated

in Figure 17 and is applied in each process step risk assessment.

Step – 1

Identify Drug product CQAs

Step – 2

Identify intermediate CQAs that impact drug

product CQAs

Step – 3

Identify material attributes and process parameters that may impact intermediate

CQAs of process step

The Initial assessment of risk for overall manufacturing process is shown in Table No. 41 and

justifications are provided in Table No. 42. Previous experience with these process steps was

used to determine the degree of risk associated with each process step and its potential to impact

the CQAs of the finished drug product.



Table No. 41: Initial assessment of risk for manufacturing process for Generic Memantine HCl ODT 10mg

Drug Product CQAs

Dry Mix

Granulatio

n

Drying

Sifting &Millin

g

Pre- lubricatio

n Blending

Lubricatio

n

Compressio

n

Assay Low Low Low Low Low Low low Content Uniformity

Hig h

Low

Low

Low

High

High

High

Dissolution Low Medium Low Low Low High High Degradatio n Products

Low

Low Mediu

m

Low

Low

Low

Low

Table No. 42: Justification for the Initial assessment of risk for manufacturing process

for generic Memantine HCl ODT 10 mg

Process Steps Drug Product

CQAs

Justification

Dry mix

Assay

As the drug load in RMG is (About 7.265%). The risk is

low.

Blend Uniformity

Dry mix process variables may impact mixing of drug

substance which, in turn, affects BU. The risk is high.

Dissolution Dry mix process variables are unrelated to Dissolution

and degradation of product. The risk is low. Degradation

Products

Granulation

Assay Uniform distribution of drug substance which affects

assay and BU is controlled by dry mix. Hence the risk is

low.

Blend Uniformity

Dissolution

Granulation can impact density and plasticity of the

granules, thus impacting compressibility of the granules,

hardness of the tablet and ultimately Dissolution. But

Memantine HCl is highly soluble drug and hence risk is

medium.




CQAs

Justification

Degradation

Products

Granulation process variables are unrelated to the

degradation products. The risk is low.

Drying

Assay Drying is unlikely to impact Assay, Blend Uniformity

and Dissolution. The risk is low. Blend Uniformity

Dissolution

Degradation

Products

During drying, wet granules are exposed to temperature

which may impact degradation of drug product. Since,

the forced degradation data shows that Memantine HCl

is not sensitive to temperature. Hence the risk is

medium.

Sifting and

Milling

Assay

The sifting and milling step controls the final granule

size distribution. A suboptimal distribution may affect

flow, causing variable tablet weight and assay during

compression. Use of appropriate sieve and screen size

will control the granule size and hence the risk is Low.

Blend Uniformity

During milling if excessive fines generates, both bulk

density and flowability of the blend may be impacted.

Since drug is uniformly distributed within the blend,

hence, during milling blend uniformity of Memantine

HCl is not impacted, hence risk is low.

Dissolution

A large amount of fines may impact tablet hardness and

Dissolution. However selection of sifter mesh size and

mill screen orifice size based on development studies

may produce consistent granules distribution and

dissolution. Hence risk is considered as low.

Degradation

Products

Sifting and milling is unlikely impact the degradation

product, hence the risk is low.




CQAs

Justification

Pre-

lubrication

Blending

Assay The granule uniformity which affects assay and BU is

controlled by earlier steps (granulation followed by

sifting and milling). Risk for Assay is low. However, this

step is to blend the sized dried granules with

extragranular excipients which in turn distributes the

granules and fines uniformly in the blender which likely

to impact the BU. The risk is high for BU.

Blend Uniformity

Dissolution Blending is unlikely to impact Dissolution. The risk is

low. Degradation

Products

Lubrication

Assay

The granule uniformity which affects assay and BU is

controlled by earlier steps (Dry mix as well as

granulation followed by sifting and milling and pre-

lubrication blending). Risk for Assay is low. However,

this step is to blend the pre- lubricated blend with little

amount of lubricants which in turn distributes the

granules and fines uniformly in the blender which likely

to impact the BU. The risk is high for BU.

Blend Uniformity

Dissolution

Lubrication process may impact the dissolution from the

tablet dosage form, hence the risk is considered as High.

Compression

Assay

In extreme cases, tablet weight variability beyond limit

can lead to-out of-specification assay results. But the

flow property of blend is very good, so the weight

variation within the specification doesn’t impact assay

results. The risk is low.

Uniformity of

Dosage units (UOD)

Compression process variables such as press speed can

cause tablet weight variation which could cause tablets




CQAs

Justification

to fall out-of specification for UOD. The risk is high.

Dissolution

Tablet hardness may impact the Dissolution. The risk is

high.

Degradation

Products

Compression is unlikely to impact degradation of

product; therefore, the risk is low.

Dry Mixing

Initial Risk Assessment of Dry Mix Process Variables

The initial risk assessment of the overall manufacturing process presented in Table No. 41

identified the risk of dry mix step to impact blend uniformity as high. So, blend uniformity was

identified as an intermediate CQA of dry mix step. Process variables that could potentially impact

blend uniformity were identified and their associated risk was evaluated in Table No 43.

Table No. 43: Initial Risk Assessment of Dry mix Process Variables

Processing Step: Dry mix

Output Material CQA: Blend Uniformity

Variables

Risk

Assessment


Input Material Variables

Memantine

HCl PSD

Low

A small particle size and a wide PSD may adversely impact

blend flowability. In extreme cases, poor flowability may cause

an assay failure. The manufacturing process is wet granulation

that suggests less impact on BU. The risk is low.

Memantine

HCl

flowability

Low

The Compressibility index value of Memantine HClis 45.83 %

suggested poor flow which could impact BU. The

manufacturing process is wet granulation that suggests less

impact on BU. The risk is low.

Memantine

Low Memantine HClis non-sticky in nature that suggests no impact



Processing Step: Dry mix


Variables

Risk

Assessment


HCl

cohesiveness

on BU. The risk is low.

Excipients

moisture

content

Low

The moisture content of excipient is controlled as per the

compendia/in-house specification. Excipient moisture content

unlikely to impact on BU as the process is wet granulation. The

risk is low.

Excipients

Flowability

Low

Since the manufacturing process is wet granulation, excipient

flowability could not impact BU. The risk is low.

Excipient Bulk

Density

Low

Since the Microcrystalline Cellulose, Mannitol, and

Crospovidone have a comparable density and their bulk

densities are unlikely to impact BU. The risk is low.

Excipients lot

to lot

Variability

Low

Large variations in the PSD of the excipients could impact BU;

however, the literature knowledge with the chosen excipients

grades has shown that the lot to lot variability within grade is

minimal. The risk is low.

Process Variables

Mixing time

High

Under- or over-mixing in Blender will result in suboptimal BU.

The risk is high.

Environment

(Temperature

and RH)

Low

If not controlled, fluctuations in the facility temperature and RH

could impact BU. Routine environment temperature and RH set

point in the CGMP manufacturing facility will be at NMT 25 ºC

and NMT 55 % RH respectively, and will be monitored during

manufacturing. The risk is low.



Initial Risk Assessment of Granulation Process Variables

The initial risk assessment of the overall manufacturing process presented in Table No. 41

identified the risk of granulation step to impact dissolution is medium. So, impact dissolution was

identified as an intermediate CQA of granulation step. Process variables that could potentially

impact dissolution were identified and their associated risk was evaluated in Table No 44.

Table No. 44: Initial Risk Assessment of Granulation Process Variables

Granulation

Output Material CQA: Dissolution

Variables

Risk

Assessment


Input Materials Variables

Purified Water

(Granulating Fluid)

Medium

The quantity of granulating fluid impact the

granulation which in turn impact dissolution. Being

Memantine HClis highly soluble drug, the risk is

medium.

Process Variables

Kneading time

Medium

Kneading time impacts the granules size distribution

which in turn may affects dissolution. Risk is

medium. Increase the granulation time will impact the

density of granules which in turn impact dissolution.

Being Memantine HCl is highly soluble drug, the risk

is medium



Optimization of Water (Granulating fluids) level in the Formulation




1 Memantine HCl * 14.53 14.53 14.53



35.00

35.00

35.00


5 Glycine USP 4.00 4.00 4.00

6 Purified Water # 0.111 0.100 0.122

Extragranular


5.50

5.50

5.50


10.00

10.00

10.00

9 Aspartame

5.00

5.00

5.00


1.00

1.00

1.00


6.00

6.00

6.00

Lubrication













2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Effect of Kneading Time in granulation:

Trials were carried out on 10 mg strength to understand the impact of granulation time. The

lubricated blend is evaluated for particle size distribution, density and finally tablets were

evaluated for hardness and dissolution.


Sr. No.

Strength % Granulating fluid Kneading Time (min) 3 5 7

B. No. ME-28 ME-29 ME-30

A. Intra Granular mg/tab mg/tab mg/tab 1. Memantine HCl * 14.530 14.530 14.530

2. Mannitol 60(Pearlitol 160C) 92.970 92.970 92.970

3. Microcrystalline cellulose (Avicel PH 101 35.000 35.000 35.000

4. Pregelatinized starch (Lycatab C)

20.000

20.000

20.000

5. Glycine 4.000 4.000 4.000

6. Purified Water # q.s q.s q.s

B. Extr a granular

7. Microcrystalline cellulose (Avicel PH 102)

5.500

5.500

5.500

8. Crospovidone (Polyplasdone XL 10)

10.000

10.000

10.000

9. Aspartame 5.000 5.000 5.000

10. Peppermint Flavour 501500TP0504 1.000 1.000 1.000

C. Lubrication 11. Silicon dioxide

(Syloid 244 FP) 6.000 6.000 6.000

12. Magnesium stearate 6.000 6.000 6.000 Core Tablet Weight 200.00 200.00 200.00












2. Granulation:


3. Drying:





5. Blending:




6. Lubrication:


7. Compression:




Initial assessment of risk for Drying Variables

The risk reduction for the drying step as a result of the development studies. Justification of

reduce risk is provide in below table 46.

Table No 47: Justification of reduce risk of the Drying Variables

Drying

Output Material CQA: Granule Density and Granule Flowability, Loss on

Variables Risk Assessment Justification and Initial Strategy

Input Material Attr ibutes

Wet Granules

Quality

Low

LOD of granules were optimized in between 1.0 to

2.5% w/w (at 105°C for 5 mins) to get desired

granules and hence risk is reduced from medium to

low

Process Variables

Inlet Temperature

Low

Drug is stable in thermal condition as per DMF and

keeping drying temperature 60±5°C to get desired

granules and hence risk is reduced from medium to

low

Sifting and Milling Initial assessment of risk for Sifting and Milling Process Variables

The Initial assessment of risk for overall manufacturing process is presented in Table No. 40.

The risk of sifting and milling step to impact physical properties of formulation identified as

medium.



Table No.48: Initial assessment of risk for Sifting and Milling Process Variables

Process Step: Sifting and Milling Output Material CQA: Granules size distribution, Granules uniformity, Granules flowability

Variables Input Material Attributes CQAs

Risk Assessment


Input Material Variables Dried Granules Quality

Granules size distribution

Medium

The granules obtained from the granulation process followed by drying could have no impact on the granules properties and subsequently tableting properties. Risk is medium.

Granules uniformity Granules flowability

Sifter Mesh size


Medium

The sifter mesh size directly impacts PSD which can impact granule uniformity and flowability. The risk is medium.

Granules uniformity

Granules flowability

Mill Screen Orifice Size


Medium

The mill screen orifice size directly impacts PSD which can impact granule uniformity and flowability. The risk is medium.

Granules uniformity


Environment (Temperature and RH)


Low

If not controlled, fluctuations in the facility temperature and RH could impact the CQAs. Routine environment temperature and RH set point in the cGMP manufacturing facility is fixed at NMT 25 ºC and NMT 55% RH, respectively, and will be monitored during manufacturing. The risk is low.

Granules uniformity


The dried granules were sifted through #30 ASTM mesh. The retained granules on #30ASTM

mesh were milled using 1.5 mm screen and these milled granules were sifted again through

#30ASTM mesh.



Pre-lubrication Blending Process Development

Initial assessment of risk for Pre-lubrication Blending Process Variables The initial risk assessment of the overall manufacturing process presented in Table No. 41 identified the risk of the pre-lubrication blending step to impact BU is high. Table No. 49 presents the Initial assessment of risk for pre-lubrication blending step.

Table No. 49: Initial assessment of risk for Pre-lubrication Blending Process

Process Step: Pre-lubrication Blending


Variables

Risk

Assessment



Granule uniformity

Medium

The granules uniformity will have impact on blend

uniformity, hence the risk is medium.

Granule flowability

Medium

The granules flowability will have impact on blend


Process Variables

Blender type

Low

Different blender types have different mixing

dynamics. Double Cone Blender (mechanism:

Diffusion) is selected based on equipment

availability. The risk is low. However, if the blender

type (mechanism) is changed during scale-up or

commercialization, the risk should be re-evaluated.

Blending Time

High

Under or over - mixing in blender with fixed speed

for insufficient time will result in suboptimal BU.

The risk is high.

Environment

(Temperature and RH)

Low

If not controlled, fluctuations in the facility

temperature and RH could impact BU. Routine

environment temperature and RH set point in the

cGMP manufacturing facility will be at NMT 25 ºC

and NMT 55% RH, respectively, and will be



Process Step: Pre-lubrication Blending


Variables

Risk

Assessment


monitored during manufacturing. The risk is low

Blending was carried out in an Double Cone blender upto 15 minutes interval at 16 rpm. Sifted

and milled dried granules and extra granular excipients were blended in the Double Cone blender

and sampling was carried out at 10 minute &15 minutes interval to check the blend uniformity of

Memantine HCl.

Lubrication Process Development

Initial assessment of risk for Lubrication Process Variables

The Initial assessment of risk for overall manufacturing process presented in Table No. 41.

identified the risk of the lubrication step to impact BU is high. Table No.50 presents the Initial

assessment of risk for lubrication step.

Table No. 50: Initial Risk Assessments of the Lubrication Process

Process Step: Lubrication

Input Material CQA: Blend Uniformity

Variables

Risk

Assessment


Input Materials Variables

Granule uniformity

Medium

The granules uniformity will have impact on blend


Granule flowability

Medium

The granules flowability will have impact on blend


Process Variables

Blender type

Low

Different blender types have different mixing

dynamics. Double conel blender (mechanism:

Diffusion) is selected based on equipment



Process Step: Lubrication

Input Material CQA: Blend Uniformity

Variables

Risk

Assessment


availability. The risk is low. However, if the blender

type (mechanism) is changed during scale-up or

commercialization, the risk should be re-evaluated.

Blending Time

High

Under or over - mixing in blender with fixed speed

for insufficient time will result in suboptimal BU.

The risk is high.

Environment


Low

If not controlled, fluctuations in the facility

temperature and RH could impact BU. Routine

environment temperature and RH set point in the

cGMP manufacturing facility will be at NMT 25 ºC

and NMT 55% RH, respectively, and will be

monitored during manufacturing. The risk is low

Lubrication was carried out in an Double cone blender for 5 minutes interval at 16 rpm.

Blended materials and extragranular lubricant (magnesium stearate ) were blended in the Double

Cone blender and sampling was carried out at 2 minute, 3 minute and 4 minutes intervals to

check the blend uniformity of Memantine HCl.

Tablet Compression Process Development

Initial assessment of risk for Tablet Compression Process Variables

Based on the Initial assessment of risk for overall manufacturing process shown in Table No. 40,

the risk of the compression step to impact Uniformity of Dosage Units (UOD) 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

assessment of risk for compression process variables are summarized in Table No. 50



Table No. 51: Initial assessment of risk for Compression Process

Process Step: Compression Output Material CQA: Uniformity of Dosage Units and Dissolution

Variables

CQAs Risk

Assessment



Blend Uniformity


Low

The lubricated blend demonstrated acceptable BU (% RSD < 5 %) during the lubrication process development. Therefore, the risk is low. Dissolution

Blend Flowability


Low

Blend flowability could impact powder flow from the hopper to the feed frame and, ultimately, to the die cavity. However, adequate flow was achieved after wet granulation. The additional extragranular diluents and lubricant also improve blend flowability. The risk is low.

Dissolution

Process Variables Press type and number of stations used


Low

The press type was selected based on equipment availability and 16 stations will be used during development. Thus, the risk is low.

Dissolution

Tooling Design


Low

Tooling design was selected based upon the size and shape of the Reference Product and it is fixed for this product, hence tooling design does not impact the UOD and dissolution. The risk is low.

Dissolution

Tablet Hardness


Low

The tablet hardness would not impact the UOD, the risk is low. Dissolution will be impacted by tablet hardness, hence risk is high

Dissolution

High

Press Speed (Dwell Time)


High

A faster than optimal press speed may cause inconsistent die filling and weight variation which may then impact UOD , hence risk is high, however dissolution may not be impacted by the tablet press speed, hence risk is low.

Dissolution

Low

Compression Run


High It is possible during long compression run times that the CU may drift. The risk is High.


141


Process Step: Compression Output Material CQA: Uniformity of Dosage Units and Dissolution

Variables

CQAs Risk

Assessment


Time

Dissolution

Low

It is unlikely for compression run time to cause a drift that leads to a dissolution failure. The risk is low.

Environment



Low

If not controlled, fluctuations in the facility temperature and RH could impact BU. Routine environment temperature and RH set point in the cGMP manufacturing facility will be at NMT 25 ºC and NMT 55% RH, respectively, and will be monitored during manufacturing. The risk is low

Dissolution

Blend of Memantine HCl ODT 10 mg was compressed by using 16 stations

Sejong Compression Machine at press speed at 15 RPM – 35 RPM. The tablet

press run at Low, Medium and High speed to check the UOD of Meantine HCl

ODT and Hardness adjusted at Low, Medium and High Hardness to check

impact on dissolution. summarize the physical parameters of the compressed at

different tablet press speed summarize the UOD data of tablets compressed at

different tablet press speed, summarize the impact of hardness on the physical

parameters of the compressed tablets, summarize the impact of hardness on the

dissolution and summarize the impact of compression run time on UOD.

Documents

Chapter Exprimental methods - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/64163/15... · Granulation end point Granulation Dissolution Blending Time Blending Tablets Hardness