Process Validation for Antiviral Famciclovir tablet

 

Shelendra Kumar Manglavat1, Deepak Kumawat2, Raksha Goswami2

1Modern Institute of Pharmaceutical Sciences, Gram: Alwasa, Behind Rewati Range,

Sanwer Road, Indore (MP) 453111.

2Oriental College of Pharmacy and Research, Indore (M.P.) 453555.

*Corresponding Author E-mail: smanglavat3@gmail.com

 

ABSTRACT:

Validation is consequently one element of quality assurance programs related with individual procedure. The validation batch encountered the specification of tablets. Tablets having batch size of maximum no. of tablets was successfully completed and the manufacturing critical process parameters were validated of this transferred product to show that the process was under control. The study embraces the validation of critical steps of manufacturing such as blending, compression, coating and container packing. It shall also establish the suitability of equipment’s and area used for the production. The process of manufacturing was carried as per the permitted batch manufacturing card. The all process validation batches had been manufactured and validated in full compliance with cGMP requirement.

 

KEYWORDS: Process validation, Famciclovir, cGMP.

 

 

 

1.    INTRODUCTION:

"Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics." [1]

 

1.1. OBJECTIVES OF PROCESS VALIDATION[2]:

1.     The manufacturing process, in addition to the individual equipment, must be validated.

2.     The goal is to create a robust manufacturing process that consistently produces a drug product with minimal variation that adheres to quality criteria of purity, identity, and potency.

3.     A validation plan for the manufacturing process should be drafted and executed by engineers in order to satisfy guidelines. The validation plan usually involves just a performance qualification section.

4.       Just as equipment validation, major changes after the initial validation will result in the need for subsequent revalidation. In the end, process validation will ensure a robust product that is highly reproducible over time.

5.     In the end, process validation will ensure a robust product that is highly reproducible over time.

 

1.2. ADVANTAGES OF PROCESS VALIDATION [2]:

A.    Quality Assurance:

Validation and process control are the heart of GMPs. Without validated and controlled process it is impossible to achieve quality products. Hence validation is a key element in assuring the quality of the product.

 

B.    Safety:

Validation can also result in increased operator safety. Properly calibrated, validated instruments and gauges used to reduce accident and results in safety.

 

C.    Better Customer Quality:

Through Proper validation, Market recall is avoided which result in better customer care and quality of the product.

 

D.    Cost reduction:

Through proper validation, the cost of the following process can be optimized.

1.     Preventive costs are costs incurred in order to prevent failures and appraisal costs

2.     Appraisal costs of inspection, testing and quality evaluation.

3.     Internal failure costs

4.     External failure costs that associated with a non-conformance condition after the product has left the company's ownership.

 

E.    Process Optimization:

The optimization of the facility, equipment system and closures etc results in a product that meets quality requirements at the lowest costs.

 

1.3 PROCESS VALIDATION STAGES[3]:

The Process validation activities can be described in three stages.:

Stage 1 - Process Design:

The commercial process is defined during this stage based on 100 knowledge gained through development and scale-up activities.

 

Stage 2 - Process Qualification:

During this stage, the process design is confirmed as 103 being capable of reproducible commercial manufacturing.

 

Stage 3 - Continued Process Verification:

Ongoing assurance is gained during routine production that the process remains in a state of control.

 

1.4 REGULATORY REQUIRMENTS FOR PROCESS VALIDATION[4]:

Accompanying process validation is not only a regulatory requirement, but also makes a great compact of sense from engineering as well as a business point of view. It is evident that pharmaceutical companies that are well versed in conducting process validation have a competitive advantage over those who are not. Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practices regulations for finished pharmaceuticals, 21 CFR parts 210 and 211. Several sections of cGMP regulations states, validation requirement in more specific terms. Extracts from some of the sections are: Section 211.100 sampling and testing of in process materials and drug products.

 

a.     "Control procedures shall be established to monitor the output and validate the performance of those manufacturing process that may be responsible for causing variability in the characteristics of in process material and drug products." Section 211.113 control of microbiological contamination

b.     "Suitable written procedures, design to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process."

 

1.5 PRE-REQUISITES FOR PROCESS VALIDATION[5]:

Before process validation can be started, manufacturing equipment and control instruments as well as the formulation must be qualified. The evidence on a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before an application for marketing authorization is submitted. Proper training and motivation of personnel are prerequisites to successful validation

 

1.6. QUALITY CONTROL TESTS FOR    TABLETS [6]:

Non-compendia standards:

Measurement of mechanical properties is not in covered pharmaceutical monograph. There are also a number of tests frequently applied to tablets for which there are no pharmaceutical requirement but will form a part of a manufacturer's own product specification.

 

In-Process Quality Control:

The control of the tableting process in production is concerned with the following:

·       Weight of tablet - single pan electric balance.

·       Crushing strength - controlled friability and disintegration time.

·       Tablet thickness - very thick tablet affect packaging particularly into blisters.

·       Disintegration time

·       Friability

 

As a part of Current Good Manufacturing Practice (cGMP), the production run is monitored under control chart. At regular interval the operator must sampled specified number of tablets, weigh them individually, check thickness, crushing strength and all the properties as mentioned above. The process can be automated and interfaced with printer. Such data promotes process improvement.

 

2.     RESEARCH ENVIZAGED:

The process of Famciclovir tablet using the wet granulation Technology in validation. Objective of this exercise is to develop a process validation protocol to validate the process and have documented evidence to ensure that critical process variables are checked during validation. Also to demonstrate the process capability of the product meets its predetermined specifications and quality attributes.

 

3.     SCOPE:

This protocol for the Process validation of Famciclovir tablets 500mg tablets, formulation defines the procedural aspects to be monitored although carrying out Process validation activity that includes prerequisites before commencing the actual work like, Master formula and process, approved purveyors and characteristics of raw materials.

 

4.    MATERIALS AND METHOD:

4.1. Materials:

Famciclovir, Lactose Anhydrous, Sodium Starch Glycolate (Type A), Hydroxy Propyl Cellulose, Magnesium Stearate, Opadry White, Purified Water is provided by Macleods Pharmaceuticals Limited, Daman Unit-2.

 

4.2 Manufacturing procedure:

4.2.1 Sifting:

Famciclovir was sifted through #40 ASTM (American Society of Testing and Materials) sieve (#425 u) using a Vibro sifter. Lactose was sifted Anhydrous through #40 ASTM sieve (#425u) using a Vibro sifter. Sodium starch Glycolate was sifted through #40 ASTM sieve (#425u) using a Vibro sifter.

 

4.2.2 Dry mixing:

The ingredients were mixed in RMG for 7 min at slow speed Agitator.

 

4.2.3 Granulation:

Dissolve Hydroxypropyl cellulose in purified water under stirring and stir to form clear solution. Add binder solution to the blend in RMG and grind at slow speed with impeller. After addition of binder solution, start impeller and chopper intermittently slow /fast speed till granules of required consistency is obtained. If required add additional quantity of purified water to get required consistency of granules.

 

4.2.4 Drying:

The wet granules were dried in fluid bed dryer at an inlet temperature of 550C- 650C till the desired LOD is achieved (LOD limit: 0.9% w/w to 1.5 % w/w at 700C).

 

4.2.5 Size reduction:

The dried granules were sifted though #20 ASTM sieve (#850 u). Mill the retained granules through 2.0mm screen fitted on multimill at fast speed knife forward direction and sift the milled granules though #20 ASTM sieve (#850 u). The sample sent to QC for particle size distribution test for milled granules (Limit-#20 ASTM sieve pass NLT 95%, #60 ASTM sieve retains NLT 25 % and NMT 60%, #100 ASTM sieve passed NMT 60%)

 

4.2.6 Pre lubrication:

Lactose anhydrous was sifted though # 40 ASTM sieve (#425 u). Low substituted Hydroxypropyl cellulose was sifted though # 40 ASTM sieve (#425u). Sodium starch glycolate was sifted though # 40 ASTM sieve (#425 u). The sifted ingredients were transferred in low shear blender and mix for 10 minutes at slow speed.

 

4.2.7 Lubrication:

Magnesium stearate was sifted through #60 ASTM sieve (#250u). Transfer the sifted magnesium stearate in low shear blender and mix for 3 minutes at slow speed.

 

4.2.8 Combination Analysis:

Intimate the quality assurance Department for sampling and quality control Department for analysis of blend as per current in process specification.

 

4.2.9. Compression:

The approved blend was compressed on rotary compression machine as per following

 

For 500 mg strength:

18mm X 8.5mm oval shaped, concave punches having "ML72" embossed on upper punch and plain on lower punch.

 

4.2.10 Coating:

Preparation of coating dispersion:

Preheat the bed of core tablets to a temperature of 45OC to 55OC. Spray the coating solution on the rolling tablet. Continue spraying till the target weight buildup of 13.2mg ± 2mg for 500mg is achieved on core tablet of 660mg.

 

5.    RESULTS AND DISCUSSION:

Table 5.1. Batches under validation

Sr. No

Batch No.

Manufacturing Date

Expiry Date

1

A

09/2017

08/2019

2

B

10/2017

09/2019

3

C

11/2017

10/2019

 

Table 5.2. Master formula Batch size: 112500 Tablets

Sr. No.

Components

Specification

Weight / Tablet in

500 mg

Dry mixing

1.

Famciclovir

HIS

500.000

2.

Lactose anhydrous (Super tab 21AN/DMV-Fonterra)

USP NF / Ph Eur

10.200

3.

Sodium starch Glycolate

(Type A, Glycolys/Roquette)

 

USP NF / Ph. Eur

 

13.800

Granulation

4.

Hydroxy Propyl cellulose

(Klucel LF Pharma/Hercules {Aqualon})

USP NF / Ph. Eur

6.600

5.

Purified Water #

HIS

150.000

Lubrication

6.

Lactose Anhydrous (Supertab 21 AN/ DMV-Fonterra)

USP NF / Ph. Eur

93.700

7.

Low-Substituted Hydroxy Propyl cellulose (L-HPC-

LH-11/Shin Etsu)

USP NF / HIS

16.500

8.

Sodium starch Glycolate (Type A, Glycolys/Roquette)

USP NF / Ph. Eur

12.600

9.

Magnesium stearate (Vegetable origin/Ferro)

USP NF / Ph. Eur

6.600

 

5.1. ENVIRONMENTAL CONDITIONS:

The environmental conditions during the manufacturing of famciclovir granules were monitored and recorded stage wise. The stage wise temperature and relative humidity readings are tabulated below.

 

Recommended conditions:

Temperature: 23 ± 2°C Relative humidity: 45 ± 5%

 

Table 5.3 Observation table for temperature

Sr. No.

Unit operation

Observation of Temperature (°C)

A B C

1

Dispensing

22

22

23

2

Sifting

22

23

22

3

Granulation

23

22

22

4

Drying

24

24

22

5

Sifting andmilling

22

22

24

6

Blending

23

22

23

7

Compression

22

23

22

8

Coating

23

22

22

 

Table 5.4 Observation table for humidity

Sr. No.

Unit operation

Observation of Relative Humidity (%)

A B C

1

Dispensing

45

47

48

2

Sifting

47

48

45

3

Granulation

48

47

46

4

Drying

46

44

45

5

Sifting andmilling

46

48

49

6

Blending

47

49

47

7

Compression

47

48

49

8

Coating

46

45

47

 

Table 5.5. Usage of raw material (active):

Active Material

B.No.

Assay

LOD

Famciclovir IHS

A

99.8

0.189

B

99.8

0.189

C

99.7

0.169

Limit

98.5 – 102.0%

NMT 0.5 % w/w

 

5.3. DRY MIXING:

Dry mixing profile:

Name of Equipment: Rapid Mixer granulator (150 Liters)

 

Equipment make: Kevin

Time of mixing: 7 minutes

Agitator speed: Slow

 

 

Table 5.6. Weight Required for Dry Mix

Sample

Weight required

(g)

Weight taken (g)

B. No. A

B. No. B

B. No. C

Lot I

Lot II

Lot I

Lot II

Lot I

Lot II

Composite

50 +3 g

50 +3 g

50 +3 g

50 +3 g

50 +3 g

50 +3 g

50 +3 g

 

 

Table 5.7 Result of Bulk Density (Dry Mix)

Batch

No.

Lot

Tapped Bulk

Density

Untapped Bulk Density

LOD at 70oC IR Balance

A

I

0.64

0.46

1.01

II

0.64

0.48

0.74

B

I

0.63

0.48

1.33

II

0.63

0.47

1.96

C

I

0.62

0.45

1.02

II

0.63

0.46

1.01

Acceptance Criteria

 For Record

 

 

5.4. GRANULATION:

Granulation process profile:

Name of Equipment: Rapid Mixer granulator (150 Liters)

 

Equipment make: Kevin

Speed of the mixer: Slow speed till dough mass of suitable consistency is obtained.

Impeller If required runs the mixer at high speed for sometime.

 

Table 5.8. Wet granulation:

Operation

RESULLllLTLTS

Mixing

Batch No.: A

Batch No.: B

Batch No.: C

Lot-I

Lot-II

Lot-I

Lot-II

Lot-I

Lot-II

Total amount of binder

8.81 kg

8.81 kg

8.81 kg

8.81 kg

8.80 kg

8.79 kg

Binder addition time

01 min

01 min

01 min

01 min

01 min

01 min

Additional amount purified water added (if any)

0.80 kg

0.90 kg

0.80 kg

0.90 kg

0.90 kg

0.90 kg

Ampere reading at end point

Agitator (8±1)

8.5 A

8.5 A

8.5 A

8.5 A

8.3 A

8.2 A

Chopper (4±1)

4.2 A

4.3 A

4.2 A

4.2 A

4.1 A

4.2 A

Total Granulation Time

04 min

 30 sec

04 min

 30 sec

04 min

 30 sec

04 min

 30 sec

04 min

 30 sec

04 min

 30 sec

 

Table 5.9: Observation of drying process

Operation

RESULTS

 

Drying

Batch No.: A

Batch No.: B

Batch No.: C

Lot-I

Lot-II

Lot-I

Lot-II

Lot-I

Lot-II

Total Drying Time (Min)

180 min

180 min

180 min

180 min

195 min

193 min

Inlet Temperature (şC)

60 to

65°C

60 to

65°C

60 to

65°C

60 to

64°C

57 to

64°C

59 to

64°C

Final Outlet Temp. (şC)

51°C

51°C

51°C

51°C

51°C

51°C

 

Table 5.10. Results for After Drying Granules

Sample

Weight

Required (g)

Weight taken (g)

Batch No. A

Batch No. B

Batch No. C

Lot I

Lot II

Lot I

Lot II

Lot I

Lot II

T1

2 – 5 g

2.132

2.036

2.033

2.155

2.183

2.059

T2

2 – 5 g

2.036

2.039

2.060

2.133

2.090

2.088

M1

2 – 5 g

2.026

2.136

2.240

2.259

2.192

2.060

M2

2 – 5 g

2.048

2.164

2.261

2.297

2.098

2.046

M3

2 – 5 g

2.127

2.016

2.076

2.261

2.108

2.026

B1

2 – 5 g

2.073

2.076

2.079

2.087

2.056

2.013

B2

2 – 5 g

2.049

2.032

2.099

2.102

2.103

2.433

 

Table 5.11. Result of Lod Of Bulk Samples (Dried Granules)

Sample

Acceptance

Criteria

Results of LOD in % w/w

Batch No. A

Batch No. B

Batch No. C

Lot I

Lot II

Lot I

Lot II

Lot I

Lot II

T1

Limit:

0.9-1.5

% w/w

1.43

0.93

1.18

1.07

1.28

1.21

T2

1.35

1.33

1.07

1.04

1.35

1.30

M1

1.00

1.04

1.12

1.24

1.14

1.02

M2

Limit:

0.9-1.5

W/V

% w/w

1.28

1.11

1.19

1.18

1.14

1.27

M3

1.37

1.29

1.06

0.97

1.29

1.23

B1

1.21

1.06

1.30

0.96

1.07

1.04

B2

1.27

1.03

1.43

1.14

1.43

1.19

Average

1.27

1.11

1.19

1.09

1.24

1.18

 

Table 5.12 Result of Sieve Analysis (Milled Granules)

Sieve

Size

Micrometer

Acceptance

Criteria

% w/w

Batch No.: A

Batch no.: B

Batch no.: C

Lot I

Lot II

Lot I

Lot II

Lot I

Lot II

20#

850 µm

Pass through #20- NLT 95%Retention on #60 – NLT 25 to NMT60% Pass through

#100- NMT  60%

99.34

99.43

98.24

98.58

98.95

99.07

60#

250 µm

42.55

42.67

47.38

46.93

36.55

39.51

100#

150 µm

34.30

33.50

35.28

33.94

46.60

44.04

 

Table 5.13. Results for Lubricated Blend

Sample

Batch No. A

Batch No. B

Batch No. C

3 min

3 min

3 min

Weight taken (g)

% Assay

Weight taken (g)

% Assay

Weight taken (g)

 % Assay

T1

1.548

98.4

1.600

99.3

1.642

99.5

T2

1.547

98.1

1.630

99.3

1.629

98.9

T3

1.519

98.2

1.632

98.1

1.653

99.0

T4

1.532

98.5

1.614

98.6

1.653

98.9

M1

1.536

97.7

1.646

98.5

1.651

99.3

M2

1.544

98.0

1.659

99.5

1.640

99.4

M3

1.548

98.3

1.652

98.2

1.672

98.8

B1

1.537

97.8

1.619

98.0

1.655

98.3

B2

1.545

97.0

1.626

97.8

1.686

98.6

B3

1.542

98.3

1.655

97.9

1.675

98.5

Min

 

97.0

 

97.8

 

98.3

Max

98.5

99.5

99.5

Mean

98.0

98.5

98.9

RSD

0.46

0.65

0.40

 

Table 5.14. Result of Sieve Analysis (Lubricated Granules)

Sieve

Analysis

Micrometer

Acceptance

Criteria

% w / w Retention

B. No. A

B. No. B

B. No. C

 60#

250 µm

 For Record

 29.41

 32.79

 32.46

 100#

 150 µm

 22.27

 20.16

 20.36

 

Table 5.15. Percentage Batch yield at the end of lubrication:

Batch no.

%Yield

Limit*

A

98.05

*NLT 98.0%

B

97.86

C

98.02

Yield Limit is tentative and will be finalized after 10 or more production batches

 

Table 5.16. Individual In-Process Test Data during Compression:

Sr.No.

Parameter

Approximate sample size

Specification

 1

Appearance

30 tablets

White to off white, oval shaped, biconvex uncoated tablets engraved with “ML 72 “on one side and plain on other side.

 2

Weight of 30 tablets

30 tablets

19.80 g + 2.0 %

(19.40 g – 20.20 g)

 3

Average Weight

30 tablets

660.0 mg + 2.0 % (646.8 mg - 673.2 mg)

 4

Uniformity of weight

30 tablets

660.0 mg ± 5.0 % (627.0mg – 693.0 mg)

 5

Thickness

30 tablets

5.50 mm + 0.20 mm

(5.30 mm - 5.70 mm)

 6

Hardness

6 tablets

170 ± 50 N (120 – 220 N)

 7

Disintegration time (With Disc)

6 tablets

NMT 15 minutes

 8

Friability

9 tablets

(Approx 6.5 g)

NMT 1.0% w/w

9

Length**

30 tablets

18.00 mm ± 0.20 mm

10

Width**

30 tablets

8.50 mm ± 0.20 mm

11

Capability Index

30 tablets

Not less than 1.33

 

 

Table 5.17. Results of Thickness

Thickness

Stage of Sampling

Batch no. A

Batch no. B

Batch no. C

Min

Max

Min

Max

Min

Max

Minimum Hardness

5.51

5.62

5.52

5.65

5.50

5.64

Maximum Hardness

5.49

5.56

5.42

5.55

5.47

5.52

Minimum Speed

5.50

5.65

5.49

5.60

5.51

5.58

Maximum Speed

5.54

5.62

5.53

5.60

5.51

5.60

Initial

At Optimum

Speed

5.55

5.62

5.50

5.55

5.56

5.64

Middle

5.51

5.60

5.50

5.55

5.52

5.65

End

5.50

5.58

5.49

5.54

5.55

5.61

 

 

Table 5.18 Results of Hardness

Stages of Sampling

Hardness (N)

Mean

Batch No. A

Minimum Hardness

133

130

139

131

140

132

134

Maximum Hardness

200

186

190

185

179

180

187

Minimum Speed

155

160

159

152

151

150

155

Maximum Speed

166

162

160

157

155

153

159

Initial

At

157

160

162

163

159

158

160

Middle

Optimum Speed

160

158

155

153

166

167

160

End

 

153

156

157

169

160

158

159

Batch No. B

Minimum Hardness

129

131

130

140

135

130

133

Maximum Hardness

189

190

196

188

185

192

190

Minimum Speed

165

159

162

168

166

158

163

Maximum Speed

158

162

160

159

161

160

160

Initial

At Optimum Speed

163

169

170

168

167

166

167

Middle

160

163

164

159

162

163

162

End

168

159

162

160

163

158

162

Batch No. C

Minimum Hardness

127

138

140

132

129

133

133

Maximum Hardness

187

183

181

190

179

177

183

Minimum Speed

155

160

159

162

163

160

160

Maximum Speed

166

169

159

170

161

168

166

Initial

Optimum Speed

168

163

158

154

165

170

163

Middle

172

158

165

161

169

161

164

End

160

163

172

169

170

165

167

 

 

Table 5.19. Results of Disintegration Time

Disintegration Time (minutes, determined at 37°C ± 2°C)

Stage of Sampling

Batch no. A

Batch no. B

Batch no. C

Minimum Hardness

09 min 43 sec

09 min 40 sec

09 min 50 sec

Maximum Hardness

10 min 30 sec

10 min 26 sec

10 min 24 sec

Minimum Speed

09 min 55 sec

10 min 00 sec

10 min 10 sec

Maximum Speed

10 min 15 sec

10 min 23 sec

10 min 28 sec

Initial

At

10 min 09 sec

09 min 50 sec

10 min 26 sec

Middle

Optimum

09 min 50 sec

10 min 00 sec

10 min 19 sec

End

Speed

09 min 40 sec

10 min 11 sec

Table 5. in 54 Sec

 

Table 5.20. Results of Average weight (mg)

Average weight (mg)

Stage of Sampling

Batch no. A

Batch no. B

Batch no. C

Minimum Hardness

664.1

659.2

660.3

Maximum Hardness

662.3

660.7

661.9

Minimum Speed

660.6

660.5

661.8

Maximum Speed

661.6

660.4

661.8

Initial

Optimum

 

Speed

661.9

661.9

660.9

Middle

662.9

662.7

660.9

End

663.9

660.1

660.2

 

Table 5.21. Results of % Yield after Compression

Batch no.

 %Yield

Limit*

A

96.14

 

*NLT 97.0%

B

96.68

C

96.97

Yield Limit is tentative and will be finalized after 10 or more production batches

 

 

 

Table 5.22. In Process Analysis Report

Sr. No.

Tests

Specification

Batch No. (RESULTS)

A

B

C

1.

Description

White to off white, oval shaped, biconvex, uncoated tablets, engraved with “ML-72”.

Complies

Complies

Complies

2.

Identification

(By HPLC)

The retention time of the principal peak in the chromatogram of sample preparation

Complies

Complies

Complies

3.

Average weight (mg)

660.0 ± 2.0 % (646.8 – 673.2)

658.81

659.37

659.83

4.

Uniformity of weight

660.0 mg ± 5 % (627.0 – 693.0)

Min: 0.87

Max:0.88

Min: 0.86

Max:1.17

Min: 0.91

Max:1.11

5.

Length (mm)

18.0 ± 0.2 (17.8 – 18.2)

Min:18.02

Max:18.10

Min:18.03

Max:18.13

Min18.03

Max18.06

6.

Width (mm)

8.5 ± 0.2 (8.3 – 8.7)

Min:8.50

Max:8.60

Min:8.55

Max:8.56

Min:8.50

Max:8.60

7.

Thickness (mm)

5.5 ± 0.2 (5.3 – 5.7)

Min:5.52

Max:5.60

Min:5.51

Max:5.57

Min:5.53

Max:5.62

8.

Hardness (N)

120 to 220

Min:127

Max:161

Min:131.85

Max:156.78

Min:138.52

Max:165.49

9.

Friability (%w/w)

Not more than 1.0

0.28

0.25

0.24

10.

Disintegration Time

(min; determined at 37°C ± 2°C, with discs)

Not more than 15

12 min 12 sec

10 min 35 sec

09 min 06 sec

11.

Dissolution

(In 0.1 N HCl; 900 mL; paddle, 50 rpm; by HPLC, % of labeled amount in 30 min)

Not less than 80 (Q)

95

92

94

95

96

95

96

89

93

91

96

92

100

98

98

98

96

98

12.

Assay (By HPLC)

Famciclovir

[C14H19N5O4]

mg / tablet

% label claim

475.0 to 525.0

95.0 to 105.0

494.319

98.9

496.178

99.2

494.932

99.0

 

 

 

Table 5.23. Results of Disintegration Time

Disintegration Time (minutes, determined at 37°C ± 2°C)

Stage of Sampling

Batch no. A

Batch no . B

Batch no. C

Coating

(Lot I)

12 min 56 sec

13 min 01 sec

13 min 09 sec

Coating

(Lot II)

13 min 03 sec

12 min 59 sec

Table 5. min 02 sec

 

Table 5.24. Results of Group Weight

Group weight (g)

Stage of Sampling

Batch no. A

Batch no. B

Batch no. C

Coating (Lot I)

13.537

13.491

13.466

Coating

(Lot II)

13.472

13.486

13.480

 

 

 

 

Table 5.26 Results of Average Weight

Average weight (mg)

Stage of Sampling

Batch no. A

Batch no. B

Batch no. C

Coating (Lot I)

676.7

674.5

673.3

Coating (Lot II)

673.6

674.3

674.0

 

Table 5.27. Results of Dissolution

Stages of Sampling

Dissolution (%)

Mean

Batch No. A

Coating (Lot I)

97

97

100

98

100

99

98

Coating (Lot II)

95

96

99

99

98

96

97

Batch No. B

Coating (Lot I)

100

100

100

100

97

99

99

Coating (Lot II)

99

99

96

99

99

98

98

Batch No. C

Coating (Lot I)

97

102

104

101

103

100

101

Coating (Lot II)

100

103

98

101

104

102

101

 

Table 5.49. Results of Dissolution Profile

Time

 Interval

Cumulative %drug released (Famciclovir)

Dissolution Medium: 0.1N Hydrochloric acid

B. No.: A

%Mean

Rsd %

10 min

50

40

44

37

40

35

37

34

38

39

48

35

40

12.9

 

15 min

74

61

66

58

62

74

54

56

54

47

64

72

62

13.5

 

20 min

88

80

82

75

78

92

70

75

76

63

81

87

79

10.3

 

30 min

100

101

100

96

102

103

93

96

98

86

98

99

98

4.9

 

45 min

99

102

102

104

105

103

104

100

98

100

99

97

101

2.4

 

 

Time

Interval

Cumulative %drug released (Famciclovir)

Dissolution Medium0.1 N Hydrochloric acid

B. No.: B

Mean%

Rsd %

10 min

43

46

34

47

47

31

35

41

48

40

50

41

42

14.5

15 min

63

69

54

67

70

48

51

59

72

64

72

65

63

12.5

20 min

79

84

71

84

86

66

66

74

86

83

87

83

79

10.0

30 min

98

101

93

101

101

86

87

98

99

100

100

97

98

4.9

45 min

103

102

104

104

102

101

102

103

102

103

102

102

103

1.0

 

Time

Interval

Cumulative %drug released (Famciclovir)

Dissolution Medium:0.1 N Hydrochloric acid

B. No.: C

Mean%

Rsd %

10 min

37

45

36

33

30

34

37

35

51

55

44

54

41

21.1

15 min

57

70

56

52

49

51

56

54

69

79

65

80

61

17.1

20 min

73

87

74

67

65

65

69

70

84

95

82

96

77

14.4

30 min

97

102

99

92

90

86

91

93

101

102

103

102

96

6.2

45 min

100

100

99

101

102

101

101

102

99

101

101

100

101

1.0

 

 

 

6.    SUMMARY AND CONCLUSIONS:

Process validation describes founding documented suggestion which provides a high degree of assurance that a specific process will unceasingly produce a product meeting its predetermined specifications and quality qualities. The goal of quality system is to dependably produce products that are suitable for their intended use. Process validation is a key element in assuring that these principles and areas are met. In this study concurrent process validation was carried out for one product. In tablet dosage form, critical parameters were taken up for validation studies.

 

The product Famciclovir tablets 500 mg was manufactured as validation batch with batch size 112500 tablets as per details summarized below.

 

In manufacturing of tablet dosage form, the critical steps are:

·         Dry mixing

·         Granulation

·         Drying

·         Blending/Lubrication

·         Compression

·         Coating

·         Bulk packing

 

The process of manufacturing was carried as per the approved batch manufacturing card. The all process validation batches had been manufactured and validated in full compliance with cGMP requirement.

 

Based on the results of the validation data of three consecutive batches, it shall be concluded that the manufacturing process used for Famciclovir 500 mg tablets consistently produces the product of pre-determined quality parameters. The Process validation showed that there was no significant batch-to-batch variation and all the process variables were studied and it showed consistent and reproducible results. Therefore it can be concluded that the process stands validated and the data can be used in directing submission

 

7.    REFERENCES:

1.     Guidance for Industry, “Process Validation: General Principles and Practices", January 2011.

2.     Venkata RT, Kotta KK, Leela M, Rao K and sasaikanth K, "Process validation of Citalopram Hydrobromide Tablets". Inter J. Res. Pharm. Bio. Sci., ISSN: 2229-3701. 2010, 1(2), 109-123.

3.     Phviral, "Process Validation: An Essential Process In Pharmaceutical Industry", January 2010, Pharmainfo.net Retrieved on 6th January 2012.

4.     Dashora K, Singh D and Saraf S, "Validation - The Essential Quality Assurance Tool for Pharma Industries." 3(6). Pharmainfo.net Retrieved on 6th January 2012.

5.     Jatto E and Okhamafe AO, "An Overview of Pharmaceutical Validation and Process Controls in Drug Development." Trop. J. Pharm. Res. 2002, 1(2), 115-122.

6.     Lachman L., Liberman HA. And Kanig JL. The Theory and Practice of Industrial Pharmacy; 3rd Edn; 600 Washington Square, Philadelphia, USA,1990, pp 330-380.

 

 

 

Received on 26.04.2020          Modified on  21.05.2020         

Accepted on 29.06.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2020; 10(3):170-178.

DOI: 10.5958/2231-5713.2020.00029.X