ABOUT AUTHORS:
Mr. Diptesh A. Patel1*, Mrs. Pinkal H. Patel1, Mr. Rohit K. Patel2
1Department of Quality Assurance, Baroda college of pharmacy, Vadodara, Gujarat, India.
2Department of Quality Assurance, Kaptab Pharmaceutical, Vadodara, Gujarat, India.
*dipteshpatel88@yahoo.com
ABSTRACT
The purpose of the research investigation was to study concurrent Process Validation of Cefixime Dispersible TabletI.P. These processes should be controlled in order that the finished product meets all quality specifications. The critical process parameters were identified with the help of process capability and evaluated by challenging its lower and upper release specifications. Three initial process validation batches of same size, method, equipment and validation criteria were taken. The critical parameter involved in sifting, sizing and compression stages were identified and evaluated as per validation plan. Uniformity of mixing is optimum in 30 min as standard deviation was between ±0.20% to ±0.99%. Compression speed of 16 RPM was suitable for IPQC as % standard deviation limits was found for Thickness was ±1.8 % to ±3 %, Hardness ±16.6 % to ±37 %, Weight Variation ±0.3% to ±7.1 %, Friability ±2.4 to ±7.1 %, Diameter ±0.9 % to ±1.2 % and Disintegration time NMT 3 min. The outcome indicated that this process validation data provides high degree of assurance.
REFERENCE ID: PHARMATUTOR-ART-1890
INTRODUCTION
Validation Principles1-11:
The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. In order to meet this principle, a good understanding of the processes and their performance is important. Quality cannot be adequately assured by in-process and finished product inspection and testing but it should be built into the manufacturing processes. These processes should be controlled in order that the finished product meets all quality specifications. Therefore, building of the quality requires careful attention to a number of factors, such as the selection of quality materials/components, product and process design, control of processes, in-process control, and finished product testing. Careful design and validation of system and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.
As per the ICH guidelines defines as Process validation: ‘Process validation is the means of ensuring and providing documentary evidence that processes within their specified design parameters are capable of repeatedly and reliably producing a finished product of required quality’.
Purpose
Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. i.e. that the process is suitable and under control.
Importance of Process validation
The main advantages to be obtained from validation are assurance of quality and process optimization, both resulting in a reduction of total costs.
Assurance of Quality
Validation is an extension of the concepts of quality assurance since close control of the process is necessary to assure product quality and it is not possible to control a process properly without thorough knowledge of the capabilities of that Process Without validated and controlled processes, it is impossible to produce quality products consistently. End product testing, in the absence of validation, gives little assurance of quality for variety reasons, among which are,
1. Very limited sample size.
2. The limited number of tests performed on a sample. For example, it is impractical to test for all potential impurities or contaminants.
3. The limited sensitivity of the test.
Process Optimization
The optimization of a process for maximum efficiency, while maintaining quality standards, is a consequence of validation. Literal meaning of word to optimize is “To make as effective, perfect or useful as possible”. The optimization of the facility, equipment, systems, and processes results in a product that meets quality requirements at the lowest cost.
Reduction of quality costs
Quality costs are divided in to four categories.
They are:
a) Preventive costs.
b) Appraisal costs.
c) Internal failure costs.
d) External failure costs.
E.g.: of internal failure costs: Any validated and controlled process will result in fewer internal failures like
* Fewer rejects
* Reworks
* Re-tests
* Re-inspection
Process validation makes it possible to do the job right the first time. Also, a scientifically studied and controlled process makes it unlikely that defective products will be dispatched to market thus no recalls or market complaints.
Safety
Validation can also result in increased operation safety. eg: gaues used on equipment that designed to operate at certain temperature and pressures must be reliable i.e. they must be calibrated.
Validation Master Plan
A validation master plan is a document that summarizes the company’s overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorized standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as re-validation.
The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP’s and validation protocols and reports. The validation protocols for equipment and systems are normally divided into three segments: Installation Qualification, Operational Qualification and Performance Qualification, abbreviated as IQ, OQ, PQ. For systems and equipment, Performance Qualification is often synonymous with Validation. Depending on the function and operation of some equipment, only IQ/OQ are required. For equipment whose correct operation is a sufficient indicator of its function, and that are monitored and/or calibrated on a regular schedule (e.g. pH meter, incubator, centrifuge, freezer), the installation and operational qualifications are performed. Systems such as air, water, steam, and major equipment which perform critical support processes, such as sterilization (autoclave, oven), depyrogenation (oven or tunnel), or lyophilization, require installation, operational and performance qualifications. Each IQ, OQ, and PQ protocol provides the specific procedure to follow, information to be recorded, a set of acceptance criteria, and a list of materials, equipment and documents needed to perform the validation.
TYPES OF PROCESS VALIDATION
1. Prospective validation
2. Concurrent validation
3. Retrospective validation
4. Re-validation
1) Prospective Validation
The objective of the prospective validation is to prove or demonstrate that the process will work in accordance with validation protocol prepared for the pilot production trials. Prospective validation should normally be completed prior to the distribution and sale of the medicinal product. In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol. All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation. During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detailed testing should also be done on the final product in its package. Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified.
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2 ) Concurrent Validation
Concurrent Validation means establishing documented evidence a process does what it is supposed to do based on data generated during actual implementation of the process. Concurrent validation may be the practical approach under certain circumstances. It is important in these cases when the systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process.
3) Retrospective Validation
Retrospective Validation means establishing documented evidence a process does what it is supposed to do based on review and analysis of historical data. In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated. The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility. The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results.
For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation.
4) Re-Validation
Re-validation is usually performed to the confirmation of initial validation for a Periodic review. Re-validation provides the evidence that changes in a process and /or the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process. Revalidation becomes necessary in certain situations.
Change Control
Clearly defined procedure is required in order to control any changes in the production processes. These procedures should control all the planned changes and ensure the presence of sufficient supporting data that show that modified process will result in a product of the desired quality. Significant changes to process (e.g. mixing time, drying temperature, etc.), using new equipments with different operating parameters, etc may require the pre-approval of the process. If a change is proposed in any of the procedures, product, processes, or equipment which may impact the quality, appropriate written procedures should be in place. All changes must be formally requested, documented and proposed changes was scientifically assessed and, depending on the changes, the need of re-validation will be determined.
Phases of Process Validation
Phase 1
Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, master production documents, Process Capability.
Phase 2
Process Validation Phase (Process Qualification phase) designed to verify that all established limitsof the Critical Process Parameters are valid and thatsatisfactory products can be produced even underthe "worst case" conditions.
Phase 3
Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures.
VALIDATION PROTOCOL
A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented.
The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information:
• Objectives, scope of coverage of the validation study.
• Validation team membership, their qualifications and responsibilities.
• Type of validation: prospective, concurrent, retrospective, re-validation.
• Number and selection of batches to be on the validation study.
• A list of all equipment to be used; their normal and worst case operating parameters.
• Outcome of IQ, OQ for critical equipment.
• Requirements for calibration of all measuring devices.
• Critical process parameters and their respective tolerances.
• Description of the processing steps: copy of the master documents for the product.
• Sampling points, stages of sampling, methods of sampling, sampling plans.
• Statistical tools to be used in the analysis of data.
• Training requirements for the processing operators.
• Validated test methods to be used in in-process testing and for the finished product.
• Specifications for raw and packaging materials and test methods.
• Forms and charts to be used for documenting results.
• Format for presentation of results, documenting conclusions and for approval of study results.
According to Indian GMP (Good Manufacturing Practice), validation study is an essential part of GMP required to be done as per predetermined protocols. Prospective process validation is carried out during the development stage by means of risk analysis of the production process which is broken down into individual steps. These are then evaluated on the basis of past experience to determine whether they might lead to critical situation The risk is evaluated, the potential causes are investigated and assessed for probability & extent, the teal plan are drawn up, & priorities are set. The trial are then performed and evaluated & overall assessment is made. If the end results are acceptable the process is considered to be satisfactory. Unsatisfactory processes must be modified & improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of error occurring on the production scale. The present work deals with identification of critical stage and their consequent evaluation by challenging its upper and lower specifications.
MATERIALS
Cefixime Trihydrate (Aurobindo Pharma Ltd., Ahmadabad, India), Pregelatinized Starch( Maize Products Ltd., Ahmadabad, India), Microcrystalline Cellulose Powder( Prachin Chemical, Ahmadabad, India), Colloidal Silicone Dioxide (Aerosil)( BASF, Holland), Talcum (Gangotri Pharma Ltd., Ahmadabad, India), Magnesium Stearate ( Komal Pharma, Ahamadabad, India), Sodium Starch Glycollate (Ascot Pharma Pvt. Ltd, Vadodara, India) , Aspartum (China), Strawberry Dry Flavour and Orange Juicy Str-Dm( Lux Flavours Ltd., Mumbai, India).
ANALYTICAL INSTRUMENTS AND MANUFACTURING EQUIPMENTS:
Weighing Balance (Campbell electronics), Vernier Calliper (Mitutoyo), HPLC (Agilent Technologies), Digital Friability Tester (Campbell Electronics), Disintegration test Apparatus (Tab Machines), Bulk density apparatus (Campbell Electronics), Hardness Tester (Advance Technology), 16station compression machine (Cadmach), Mechanical Sifter (Unimek), Double Cone Blender (Kishore and Co.), Sieve Shaker (Lequitron).
Evaluation of Tablet
The critical parameters considered during the process validation of Cefixime 200mg tablets are
* Sifting
* Dry Mixing
* Compression
1. Weight variation,
2. Hardness Test,
3. Friability,
4. Thickness,
5. Diameter
6. Disintegration time
7. Assay
* Hopper Study
* Strip Packing
Sifting
Approved raw material was sifted through the sieve and integrity of sieve measured after completion of sifting, bulk density and tapped density were measured. Results were shown in Table 4.
Dry Mixing
The dry-mixing step involves mixing of active ingredients with other additives using Double Cone Blender (DCB). The content of Cefixime in the dry mix shall be tested, to validate dry mixing process. Mixing speed and mixing time were the critical variables that determine content uniformity. Mixing speed was kept constant, mixing time 10, 20, 30 min shall be studied to validate dry mixing step. Each sides sampled from top (T), middle (M), bottom (B) layer of DCB in polyethylene bag for QC analysis of assay. Refer sampling plan of DCB as shown in figure.1 Dry mixing results of all the batches were well within the acceptance criteria. Results were shown in Table 5.
Fixed parameters
Time interval studies: after 10, 20 and 30 min
Measured response: Description, blend uniformity
Acceptance criteria: Not less than 95% and not more than 105% of the Label claim
Compression of Tablets
For compression of tablets involves consistent flow of properly lubricated, powder in the hopper to dies where the powder were compressed in to tablets. Compression carried out as per batch manufacturing recorded. Collect the sample at various speed. i.e. at 16 RPM, 22 RPM, 26 RPM and carry out testing of content uniformity and physical parameters such as hardness, thickness, friability etc. Compression resulted of all the batches were well within the acceptance criteria. Results of the compression was shown in table no.6 Tablets were compressed using round Punch size 14/32”. Upper punch with break line and lower Punches plain. The specifications for tablet was Average weight 470 mg (±5%) , Hardness NLT 5 kg/cm2, Thickness 3.6 mm to 4.2 mm, Friability NMT 1%w/w, D.T. NMT 3 min, Assay 90% to 110%, Diameter 11.20 mm (±5%).
Weight Variation
20 tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets were calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weight deviate from the average weight by more than the percentage shown in Table 9.
Thickness and Diameter
10 tablets were randomly selected from each batch and there thickness and diameter was measured by using digital vernier caliper. Results are shown in Table 8.
Hardness
The crushing strength kg/cm2 of prepared tablets was determined for 10 tablets of each batch by using Visual tablet hardness tester. The average hardness and standard deviation was determined.The results are shown in Table 7.
Friability
10 tablets were weighed and placed in the friabilator and apparatus was rotated at 100 rpm. After revolutions the tablets were deducted and weighed again Table 7.The percentage friability was measured using the formula,
% F = {1-(Wt/W)} ×100
Where, % F = friability in percentage
W = Initial weight of tablet
Wt = weight of tablets after revolution.
Hopper study:
Set the level of hopper at full ,Half and End of bottom level. Cheak the IPQC parameters like Thickness, Diameter, Wt. variation, Hardness. Results of full hopper level was given in table 10-11.
Assay
Cefixime was estimated by using HPLC as per the Indian pharmacopoeia method at 254 nm formulation Samples was Subjected to HPLC.
Column: A stainless steel column 25×4.6 mm packed with octadecylsilane bounded to porous silica (5micrometer)
Mobile phase: Mixture of 30 volume of buffer solution prepare by diluting 25 ml of 0.4 M tetrabutylamonium hydroxide solution to 1000 ml with water and adjust the pH 6.5 with 1.5 M orthophosphoric acid and 10 volume acetonittril.
Flow rate: 2ml/ minutes.
Wavelength: 254 nm.
Injection volume: 20 micro liters.
Standard solution: Weighed out 10 mg of working standard in 100 ml volumetric flask and dissolve it with the mobile phase. Pipette out 5ml of standard solution and dilute with 50 ml mobile phase.
Test solution: Weighed out 400 mg of equivalent dry mix powder in 100 ml volumetric flask, add 100ml of mobile phase and dilute 5ml with 50 ml mobile phase, pH-7.
% Assay =
Sample Area × Standard Weight × Assay × Theoretical Weight
-----------------------------------------------------
Standard Area × Sample Weight
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Strip Packing
Packing is to be done as per batch packing record. In packing stage three batches i.e. Batch-1, Batch-2 and Batch-3 shall be considered for validation. Packing results of all the batches are well within the acceptance criteria. Results were shown in Table 12.
Packing Material:
- Aluminum Foil
- Carton (10 X 10)
- Shipper
- Sealing tape
- Strapping roll
Printed Foil:
- Description: 0.02 mm Aluminum Foil
- Text matter: Specimen Attached
- Width (size) : 100 mm ± 2%
- Colour : Green colour printing with red line on one side.
RESULTS AND DISCUSSION
All the results are tabulated in Table 4-11.
Quality cannot be adequately assured by in-process and finished inspections and testing but it should be built in to the manufacturing process. These processes should be controlled in order that the finished product meets all quality specifications. The quality system regulation defines process validation by establishing evidence that a process consistently produces a result or product meeting its predetermined specifications. The goal of quality system is to consistently produce products that are suitable for their intended use. In this study concurrent process validation was carried out for one product. In tablet dosage form, critical parameters were taken up for validation studies.
In tablet dosage form, the critical parameters are
* Sifting
* Dry mixing
* Compression
1. Weight variation,
2. Hardness Test,
3. Friability,
4. Thickness,
5. Diameter
6. Disintegration time
7. Assay
* Hopper study.
* Strip Packing
Sifting
Integrity of sieve was found to be satisfactory by using 40# sieve size.
Dry Mixing
The dry-mixing step involves mixing of Cefixime with other additives using Double Cone Blender. The content uniformity of Cefixime was established during validation of dry mixing process. The mixing of the active ingredient depends on the mixing of drug during mixing. Hence, it was a critical step to be validated.
Compression
The compression for all the three batches has been validated for 16 RPM, 22 RPM, 26 RPM speeds of compression machine. The physical parameters of the tablets were well within the acceptable limits. The results were comparable among all the three batches, it was given in table 6..
Hopper Study
The compression for all the three batches had been validated for Full Hopper, Half Hopper, End of the Hopper of compression machine. The physical parameters of the tablets were well within the acceptable limits.
Strip packing
Here, various measured parameter for packing process are machine speed , sealing & forming, temperatures, knurling & cutting, pocket formation. Strip packing process involves packing of tablets in aluminum foil. Temperature of sealing rollers, speed of machine is critical variables. Adequate sealing roller temperature is essential to get proper sealing, less temperature will lead to improper sealing which cause leakage and higher temperature will result in burning or spoilage of aluminum foil. Speed of the machine is influenced by following parameters. Proper sealing of strip pack configuration of strip pack Leak test and strip appearance are carried out to establish the above variables during packing operation.
Process Control Variables
Table 1: Process Control Variables
|
PROCESS |
VARIABLE |
|
Sifting |
Sieve size |
|
Dry Mixing |
Load , Speed of Mixer, Mixing Time |
|
Dry Screening |
Sieve size, Screen size , Milling speed |
|
Compression |
Speed of compression , Average weight, Uniformity of weight, Diameter, Thickness, Hardness, Friability, Disintegration time, Hopper Study |
Table 2: Details of Raw Materials
|
Sr. |
Ingredients |
Spec. |
Actual mg/1 Tab |
Qty.Per Batch |
|
|
SIFTING |
|
|
|
|
1. |
Cefixime Trihydrate(Compacted) |
IP |
229.47 |
6.196 |
|
2. |
Pregelatinized Starch |
USP |
81.00 |
2.187 |
|
3. |
Microcrystalline Cellulose |
IP |
114.52 |
3.092 |
|
4. |
Collodial Silicone Dioxide (Aerosil) |
IP |
3.00 |
0.081 |
|
5. |
Talcum |
IP |
10.00 |
0.270 |
|
6. |
Magnesium Stearate |
IP |
6.00 |
0.162 |
|
7. |
Sodium Starch Glycollate |
IP |
14.00 |
0.378 |
|
8. |
Aspartum |
IP |
7.00 |
0.189 |
|
9. |
Strawberry Dry Flavour |
IH |
3.00 |
0.081 |
|
10. |
Orange Juicy Str-Dm(Dry Flavour) |
IH |
2.00 |
0.054 |
|
|
LUBRICATION |
|
|
|
|
11. |
Talcum |
IP |
1.0 |
0.025 |
|
12. |
Magnesium Stearate |
IP |
4.0 |
0.01 |
Table 3: Equipments to be used During Validation
|
Processing Equipments |
Processing Stage |
|
Weighing Balance |
Weight variation measure |
|
Vernier Calliper |
Diameter/ Thickness measure |
|
HPLC |
Assay testing |
|
Digital Friability Tester |
Friability testing |
|
Disintegration test Apparatus |
D.T. testing |
|
Bulk density apparatus |
Density testing |
|
Hardness Tester (Dial type) |
Hardness testing |
|
16station compression machine |
Compression |
|
Mechanical Sifter |
Sifting |
|
Double Cone Blender |
Mixing |
|
Sieve Shaker |
Sieving |
HPLC- High performance liquid chromatography
Table 4: Sizing Stage Result
|
Batch No. |
% fine |
Bulk Density (gm/ml) |
Tapped density (gm/ml) |
|
Batch-1 |
40 # |
0.6529 |
0.8162 |
|
Batch-2 |
40 # |
0.5926 |
0.6972 |
|
Batch-3 |
40 # |
0.630 |
0.7876 |
Table 5: Dry Mixing Process results
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