The purpose of this work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing process with special reference to the requirements stipulated by the US Food and Drug Administration (FDA). Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. In pharmaceutical industry, Process Validation performs this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.
Keywords: Process Validation, Qualification, Good Manufacturing Practices
The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970's in order to improve the quality of pharmaceuticals. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production. 1
In a guideline, validation is act of demonstrating and documenting that any procedure, process, and activity will consistently lead to the expected results. It includes the qualification of systems and equipment. The goal of the validation is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. In general, an entire process is validated and a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time. 10
Why Is Validation Required? 5, 6
O It would not be feasible to use the equipments without knowing whether it will produce the product we wanted or not.
O The pharmaceutical industry uses expensive materials, sophisticated facilities & equipments and highly qualified personnel.
O The efficient use of these resources is necessary for the continued success of the industry. The cost of product failures, rejects, reworks, and recalls, complaints are the significant parts of the total production cost.
O Detailed study and control of the manufacturing process- validation is necessary if failure to be reduced and productivity improved.
The pharmaceutical industries are concerned about validation because of the following reasons.
O Assurance of quality
O Cost reduction
O Government regulation
O Site validation committee (SVC): Develop Site master Validation plan, Prepare/execute/approve validation Studies
O Manufacturing department: Prepares the batches as a routine Production batch
O Quality assurance: Ensure compliance, see that documentations/procedures are in place, approves protocols and reports
O Quality control: Perform testing and reviews protocol and report as needed.
Responsible Authorities For Validation6
The validation working party is convened to define progress, coordinate and ultimately, approve the entire effort, including all of the documentation generated. The working party would usually include the following staff members, preferably those with a good insight into the company's operation.
O Head of quality assurance
O Head of engineering
O Validation manager
O Production manager
O Specialist validation discipline: all areas
Responsible for manufacturing of batches and review of protocol and report.
Responsible for analysis of samples
Responsible for samples collection and
submission to QC
Providing utilities and engineering
Responsible for preparation of protocol and manufacturing of validation batches
Responsible for protocol authorization and preparation of summary report.
Elements Of Validation8, 10:-
Design Qualification (DQ): -
It is documented review of the design, at an appropriate stage of stages in the project, for conformance to operational and regulatory expectations.
DQ Check Items:
O GMPs and regulatory requirements
O Performance criteria
O Facility air flow, movement flow & pressure regimes
O Reliability & efficiency
O Commissioning requirements
O Construct ability & installation of equipment
O Maintenance & access to critical equipment & instrumentation
O Safety & environment impact
Installation Qualification (IQ): -
It is documented verification that all aspects of a facility, utility or equipment that can affect product quality adhere to approved specifications and are correctly installed.
Important IQ considerations are:
O Installation conditions (wiring,utilities, and functionality)
O Calibration, preventative maintenance, cleaning schedules
O Safety features
O Supplier documentation, prints, drawings and manuals
O Software documentation
O Spare parts list
O Environmental conditions (such as clean room requirements, temperature and humidity)
O Equipment design features (i.e. materials of construction cleanability)
Operational Qualification (OQ): -
It is documented verification that all aspects of a facility, utility or equipment that can affect product quality operate to Intend throughout all anticipated ranges.
OQ considerations include:
O Process control limits (time, temperature, pressure, line speed and setup conditions)
O Software parameters
O Raw material specifications
O Process operating procedures
O Material handling requirements
O Process change control
O Short term stability and capability of the process, (latitude studies or control charts)
O Potential failure modes, action levels and worst-case conditions (Failure Mode and effects
O Fault tree analysis
Performance Qualification (PQ): -
It is documented verification that all aspects of a facility, utility or equipment perform as intended in meeting predetermined acceptance criteria.
PQ considerations include:
O Actual product and process parameters and procedures established in OQ
O Acceptability of the product
O Assurance of process capability as established in OQ
O Process repeatability, long term process stability
Process Validation: -
Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation is a requirement of current Good Manufacturing Practices (GMPs) for finished pharmaceuticals (21CFR 211) and of the GMP regulations for medical devices (21 CFR 820) and therefore applies to the manufacture of both drug products and medical devices. Process validation involves a series of activities taking place over the lifecycle of the product and process.10
The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation: - "PROCESS VALIDATION" is establishing documented evidence which provides a high degree of assurance that a specific process consistently produces a product meeting its predetermined specifications and quality attributes"4,10
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.
Types Of Process Validation 3, 10: -
The guidelines on general principles of process validation mentions four types of validation:
A) Prospective validation (or premarket validation)
B) Retrospective validation
C) Concurrent validation
A) Prospective validation:
Establishing documented evidence prior to process implementation that a system does what it proposed to do based on preplanned protocols. This approach to validation is normally undertaken whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences. In fact, validation of a process by this approach often leads to transfer of the manufacturing process from the development function to production.
B) Retrospective validation:
Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process. Validation of these facilities, processes, and process controls is possible using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. Therefore, this type of validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of product, operating processes, or equipment.
This approach is rarely been used today because it's very unlikely that any existing product hasn't been subjected to the Prospective validation process. It is used only for the audit of a validated process.
C) Concurrent validation:
Concurrent validation is used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual imputation of the process. This approach involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control.
Revalidation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data. This approach is essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems. Possible reasons for starting the revalidation process include:
O The transfer of a product from one plant to another
O Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality
O The necessity of periodic checking of the validation results
O Significant (usually order of magnitude) increase or decrease in batch size.
O Sequential batches that fail to meet product and process specifications.
O The scope of revalidation procedures depends on the extent of the changes and the effect upon the product.
Change Control2, 8:
Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations.
All changes must be formally requested, documented and accepted by the validation team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined.
Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned.
The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the validation team. The team should decide if a re-validation must be conducted prior to implementing the proposed change.
Phases Of Process Validation8, 10, 11: -
The activities relating to validation studies may be classified into three phases:
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, installation qualification, master production documents, operational qualification, process capability.
Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the critical process parameters are valid and that satisfactory products can be produced even under the "worst case" conditions.
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. At this stage the validation team also assures that there have been no changes/ deviations that should have resulted in requalification and revalidation.
Validation Protocol3, 4, 8: -
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.
The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted.
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:
2. Objective & Scope
4. Protocol Approval
5. Validation Team
6. Product Composition
7. Process Flow Chart
8. Manufacturing Process
9. Review of Equipments / Utilities
10.Review of Raw Materials and Packing Materials
11. Review of Analytical and Batch Manufacturing Records
12. Review of Batch Quantities for Validation (Raw Materials)
13. Review of Batch Quantities for Validation (Packing Materials)
14. HSE Requirements
15. Review of Process Parameters
16. Validation Procedure
17. Sampling Location
19. Acceptance Criteria
Validation Master Plan4, 7, 8
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 include the list/inventory of the items to be validated and 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 format and content should include:
o introduction: validation policy, scope, location and schedule
o organizational structure: personnel responsibilities
o plant/ process /product description: rational for inclusions or exclusions and extent of validation
o specific process considerations that are critical and those requiring extra attention
o list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach
o re-validation activities, actual status and future planning
o key acceptance criteria
o documentation format
o reference to the required SOP's
o Time plans of each validation project and sub-project.
Process Overview Of Tablet Manufacturing6
Process Critical Parameters During Process Validation Of Tablet Manufacturing Process2, 9, 10, 11
Kneading during Binder addition
Kneading at slow Speed after Binder addition
Kneading at slow speed
Screen Integrity before and after use
Product bed temperature
Screen Integrity before and after use
Screen integrity before and after use
RPM of cage blender
Yield of lubricated granules
Granules flow from granule's container to Feeder
Machine Overload pressure
Weight of 20 tablets
Individual weight variation
Spray Nozzle Aperture
Temperature of Inlet air
Temperature of Exhaust air
Coating Pan RPM
Distance Between gun & tablet bed
Average Weight gain
Sealing Roller Temperature
From study, it can be stated that Process validation is a major requirement of cGMP regulation for finished pharmaceutical products. It is a key element in assuring that the quality goals are met. Successfully validating a process may reduce the dependence upon intensive in process and finished product testing.
Finally, it can be concluded that Process validation is a key element in the quality assurance of pharmaceutical product as the end product testing is not sufficient to assure quality of finished product.
TheCorresponding author would like to thank Dr. Anil M. Pethe, Head of Department of Quality Assurance, SPTM, NMiMS, Shirpur for his constant help, unflinching guidance, critical comments and helpful suggestions.
1.Agalloco J. Validation: an unconventional review and reinvention. PDA J. Pharm. Sci. Tech. 49:175-179 (1995).
2.Aleem H, Zhao Y, Lord S, McCarthy T and Sharratt P. Pharmaceutical process validation: an overview. J. Proc. Mech. Eng. 217: 141-151 (2003).
3. Chitlange S. S, Pawar A. S, Pawar H. I, Bhujbal S. S. and Kulkarni A. A. Validation. http://www.pharmainfo.net/reviews/validation . 4: 318-320 (2006).
4. Dashora K, Singh D and Saraf S. Validation - the Essential Quality Assurance Tool for Pharma Industries. www.pharminfo.net. 3: 45-47 (2005).
5. Guidance for Industry: Process Validation: General Principles and Practices. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), November 2008.
6.Gupta G. D, Garg R and Aggarwal S.Guidelines on General Principles of Validation: Solid, Liquid and Sterile dosage forms. www.pharminfo.net . 6: 28-33 (2008).
7. Haider S. I. Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance. CRC Press LLC, Boca Raton, Florida.
8.Lambert J. Validation Guidelines For Pharmaceutical Dosage Forms. Health Canada / Health Products and Food Branch Inspectorate, 2004:7-15.
9.Lingnau J. Optimization and Validation of Manufacturing Processes. Drug Dev. Ind. Pharm. 15: 1029-1046 (1989).
10. Nash R. A. and Wachter A. H. Pharmaceutical Process Validation An International Third Edition. Revised and Expanded, Marcel Dekkar, Inc., New York, 2003; 129:760-792.
11. Virmani T and Pathak K. Validation: An Essentiality in the Pharmacy. www.Pharminfo.net. 5:22-24 (2007).
Figure No.1: General view of process validation
Figure No.2: Process validation timeline for a new process
Figure No.3: Schematic diagram of processing steps and respective in-process variables during tablet manufacture
Dr. Anil M. Pethe
SVKM's NMiMS, SPTM, Babulde, bank of Tapi River, Mumbai - Agra Road, Shirpur,Dist. Dhule, Maharashtra 425405
E-Mail: email@example.com, Phone no.: 09823792699, 09604399885