1. Introduction to validation ... 9
1.1 Definition ... 9
1.2 History of validation ... 10
1.2.1 Equipment Qualification and Process Qualification: ... 11
1.3 Why validation? ... 13
1.4 What has to be validated? ... 14
1.5 Scopes of Validation ... 15
1.6 Pre-Requisites for Successful Validation ... 17
1.7 Approaches of Validation ... 18
1.8 Phases in Validation ... 18
1.9 Validation Decision Tree: ... 20
2. Organizing for Validation ... 22
2.1 Staffing issues ... 22
2.2 Department interactions ... 22
2.3 Master planning or planning for Validation ... 24
2.4 Benefits of Master Planning ... 24
2.5 Validation Process ... 25
2.6 Validation Plan ... 25
2.7 Typical validation master plan structure ... 26
2.8 Validation Protocol ... 27
2.9 Validation set up ... 29
2.10 Relationship between validation and qualification ... 29
2.10.1 Design Qualification (DQ) ... 30
2.10.2 Installation Qualification (IQ) ... 32
2.10.3 Operational Qualification (OQ) ... 33
2.10.4 Performance Qualification (PQ) ... 34
2.10.5 Component Qualification (CQ) ... 35
2.10.6 Requalification ... 35
2.10.7 Revalidation ... 35
2
2.10.9 Change Control ... 36
2.11 Documentation ... 37
3. Areas of Validation ... 43
3.1 Process Validation ... 44
3.1.1 Pilot Scale-Up and Process Validation ... 45
3.1.2 Priority Order in Process Validation ... 46
3.1.3 Stages of Process Validation ... 47
3.1.4 Types of process validation ... 52
3.1.5 Process Validation Decision ... 59
3.1.6 Sterilization Validation ... 62
3.2 Analytical method validation ... 66
3.2.1 Why analytical methods need to be validated? ... 67
3.2.2 Types of analytical procedures to be validated ... 67
3.2.3 Advantages of analytical method validation ... 67
3.2.3 Strategy for validation of methods ... 68
3.2.4 Analytical procedure ... 68
3.2.5 Validation Parameters ... 69
3.2.6 Data Elements Required for Validation ... 76
3.3 Facilities Validation ... 77
3.3.1 The Engineering Design Process for a Facility ... 77
3.3.2 Conceptual Design: ... 77
3.3.3 Purposes: ... 78
3.3.4 Qualification Activities ... 79
3.3.5 Qualification Cost ... 79
3.3.6 Design Development: ... 79
3.3.7 Facility Qualification Plan ... 80
3.3.8 Qualification ... 81
3.4 Computer System Validation ... 86
3.4.1 History of computer system validation in brief ... 86
3.4.2 Importance of CSV ... 87
3.4.3 Typical Computer System Validation ... 87
3.4.4 Advantages of CSV ... 89
3
3.4.6 Software Life Cycle ... 90
3.4.7 Construction or coding ... 94
3.4.8 Testing by the Software Developer ... 94
3.4.9 User Site Testing ... 95
3.5 Equipment Validation ... 96
3.5.1 Reason of Equipment Validation ... 96
3.5.2 Content of Equipment Validation ... 96
3.5.3 Balances and Measuring Equipment ... 97
3.5.4 Production equipment ... 97
3.5.5 Control laboratory equipment ... 97
3.5.6 Washing, cleaning and drying equipment ... 98
3.5.7 Equipment Validation Process ... 98
3.5.8 HPLC method calibration ... 100
3.5.9 HVAC Validation ... 107
3.6 Cold Chain Validation ... 117
3.6.1 Uses ... 117
3.6.2 Strategy ... 118
3.6.3 Evaluation and Reporting... 119
3.6.4 Ongoing Monitoring ... 119
3.7 Source Validation: ... 120
3.7.1 Methods of vendor validation ... 120
3.7.2 Corrective and Preventive action ... 123
3.7.3 Importance of Source Validation ... 124
3.8 Personnel Validation ... 127
3.8.1 GMP Requirement ... 127
3.8.2 Responsibilities ... 127
3.8.3 Training for personnel ... 129
3.9 Packaging Validation: ... 130
3.9.1 Packaging Materials ... 131
3.9.2 Packaging Equipment ... 131
3.9.3 Assess the GMP Risk ... 132
3.9.4 Line Layout ... 132
4
3.9.6 Conduct of Packaging Validation ... 133
3.9.7 Performance qualification examples ... 135
3.9.8 Tests that can be performed for packaging validation ... 136
3.10 Cleaning Validation ... 139 3.10.1 Necessity ... 140 3.10.2 Advantages ... 140 3.10.3 Contamination ... 140 3.10.4 Cross Contamination ... 140 3.10.5 Mechanism of Contamination ... 141
3.10.6 Cleaning Agent selection ... 141
3.10.7 Sampling Techniques ... 142
3.10.8 Sampling Methods ... 143
3.10.9 Level of Cleaning ... 145
3.10.10 Cleaning Validation procedure ... 146
3.10.11 Strategy on Cleaning Validation Studies ... 146
3.10.12 Analyzing cleaning validation samples ... 148
3.10.13 Data analysis for estimating possible contamination ... 149
4. Future Aspects of Validation ... 150
4.1. Latest Technology ... 150 4.2 Automated Inspection/Identification ... 150 4.3 Process Automation ... 150 4.4 Robotics ... 151 4.5 Isolation... 151 5. Conclusion ... 153 6. References ... 154
5
Glossary:
1. Calibration – The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (for e.g. weight, temperature, pH), recording and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.
2. Computer validation - Documented evidence which provides a high degree of assurance that a computerized system analyses, controls and records data correctly and that data processing complies with predetermined specifications.
3. Commissioning – The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation.
4. Concurrent validation – Validation carried out during routine production of products intended for sale.
5. Cleaning validation – Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology, and equipment size.
6. Design qualification (DQ) – Documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of GMP.
7. Good engineering practices (GEP) – Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions. 8. Installation qualification (IQ) – The performance of tests to ensure that the installations
(such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications.
9. Operational qualification (OQ) – Documented verification that the system or subsystem performs as intended over all anticipated operating ranges.
10. Performance qualification (PQ) – Documented verification that the equipment or system operates consistently and gives reproducibility with defined specifications and parameters for
6 prolonged periods. (In the context of systems, the term ―process validation‖ may also be used.)
11. Process validation – Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics.
12. Prospective validation – Validation carried out during the development stage on the basis of a 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 may lead to critical situations.
13. Qualification – Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected result. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation.
14. Retrospective validation – Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged.
15. Revalidation – Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements.
16. Standard Operating Procedure (SOP) – An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specific master batch production documentation.
17. Validation – Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. The aim of validation is not to correct or detect deviations in the packed product but to prevent deviations in the final packed products as far as is practicable and economic.
18. Validation protocol (or plan) (VP) – A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process – or a part thereof – for routine use.
7 19. Validation report (VR) – A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment.
20. Validation master plan (VMP) - The VMP is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer‘s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer‘s validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan.
21. Verification – The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with the GMP principles.
22. Worst case – A condition or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.
23. URS – User Requirements Specification (URS) provides a clear and precise definition of what the user wants the system to do. It defines the functions to be carried out, the data on which the system will operate and the operating environment. The URS define also any non-functional requirements, constraints such as time and costs and what deliverables are to be supplied. The emphasis should be on the required functions and not the method of implementing those functions.
24. Acceptance Criteria – The criteria a product must meet to successfully complete a test phase or to achieve delivery requirements.
25. Change Control – A formal system of reviewing and documenting proposed or actual change that might affect the validated status of a system, equipment or process followed by action to ensure ongoing validated state.
26. Requirement – It can be any need or expectation for a system. It reflects the stated or implied needs of the customer, and may be market-based, contractual, or statutory, as well as an organization‘s internal needs.
8 28. Quality Assurance – It can be defined as the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. In addition, it ensures that arrangements made for the manufacture, supply and use of the correct starting and packaging materials.
29. Quality Control – It is the part of GMP concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensures that the necessary and relevant tests are actually carried out and that materials are not released for used, nor products released for sale or supply, until their quality has been judged to be satisfactory. It is not confined to laboratory operations but must be involved in all decisions concerning the quality of the product.
9
1. Introduction to validation
1.1 DefinitionValidation is not a one-time event but on-going process covering all phases of a product or process. Literally, validation in pharmaceuticals means to be valid or justifiable. Simply saying, validation means ‗action of proving effectiveness.‖ According to FDA 1987 ―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 attributes.‖1 According to European Commission- 1991, ―validation is an act of proving in accordance of GMPs that any process actually leads to expected results.‖ According to European Commission-2000, ―validation is documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.‖
Validation is the evaluating of processes, products or analytical methods to ensure compliance with product or method requirements. Prerequisites to fulfill these requirements for analytical laboratories are properly functioning and well documented instruments (hardware and firmware), computer hardware and software and validated analytical methods.2
Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. The basic principles of quality assurance have as their goal the production of products that are fit for their intended use. These principles are as follows:
Quality, safety and efficacy must be designed and built into the product. Quality cannot be inspected or tested into the product.
Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications.
Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications.
Documentation associated with validation includes: Standard operating procedures (SOPs)
10 Specifications
Validation master plan (VMP) Qualification protocols and reports Validation protocols and reports.
The implementation of validation work requires considerable resources such as: Time: Generally validation work is subject to rigorous time schedules.
Financial: Validation often requires the time of specialized personnel and expensive technology.
Human: Validation requires the collaboration of experts from various disciplines (e.g. a multidisciplinary team, comprising quality assurance, engineering, manufacturing and other disciplines, depending on the product and process to be validated).3
Chapman purported ―Validation means nothing else than well-organized, well-documented common sense‖.4
1.2 History of validation:
Validation is a subject that has grown in importance within the global healthcare industry over the past 25 years. Its origin can be traced to terminal sterilization process failures in the early 1970s. Individuals in the US point to the LVP sterilization problems of Abbott and Baxter, while those in the U.K. cite the Davenport incident.5 Each incident was a result of a non-obvious fault coupled with the inherent limitations of the end-product sterility test. As a consequence of these events, non-sterile materials were released to the market, deaths occurred, and regulatory investigations were launched. The outcome of this was the introduction by the regulators of the concept of ―Validation‖.
The initial reaction to this regulatory initiative was one of puzzlement, only a limited number of firms had encountered difficulties, and all of the problems were seemingly associated with the sterilization of LVP containers. It took several years for firms across the industry to understand that the concerns related to process effectiveness were not limited to LVP solutions, and even longer to recognize that those concerns were not restricted to sterile products. From its earliest days, validation was identified as a new regulatory requirement to be added to the list of things that firms must do, with little consideration of its real implications. The first efforts reflected
11 what can be termed the ―scientific method‖ of observation of an activity, hypothesis/predition of cause/effect relationship, and experimentation followed by new observations in the form of the experimental report. In the pharmaceutical validation model this has evolved into the validation protocol (hypothesis and prediction), field execution (experimentation), and summary report preparation (documented observations).6
By 1980, it was evident to all that validation was here to stay, so pharmaceutical firms began to organize their activities more formally. Ad hoc teams and task forces that had started the efforts were replaced by permanent Validation Departments whose responsibilities and scope varied with the organization but whose purpose was to provide the necessary validation for a firm‘s products and processes. The individuals in these departments were the first to grapple with validation as their primary responsibility, and their methods, concepts, and practices have served to define validation ever since as ― establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes‖.7
The first efforts at validation were rather crude and limited in their understanding of the full implications but slowly made significant strides. For e.g. the first sterilization validations were performed without prior qualification of the equipment. Once validation had been established as discipline, methods for its execution became substantially more formalized and rigorous. Perhaps, most important was stride was separation of activities into two major categories.
1.2.1 Equipment Qualification and Process Qualification:
It was apparent by then that validation had to be more closely integrated into the mainstream of cGMP operations in order to maximize its effectiveness in larger organizations. A number of areas can be identified as pre-requisites for process or system validation. The origins of these elements can be identified in the cGMP requirements for drugs and devices (Table 1).8
With this understanding, the industry began to recognize that validation offered advantages to the firm and implemented validation objectives that were non-regulatory and geared for the optimization of processes and systems. The attention being placed on validation at this time led to important changes in how firms approached its implementation and should be integrated with other GMP.
12 Table 1:- Pre-Requisites for Validation
1 Process Development [21 CFR 820.30—Design Control]. The activities performed to define the process, product or system to be evaluated.
2 Process Documentation [21 CFR 211 Subparts F - Production and Process controls and J- Records and Reports]. The documentation (batch records, procedures, test methods, sampling plans) and processes (software) that define the operation of the equipment to attain the desired result.
3 Equipment Qualification [21CFR 211 Subparts C – Buildings and Facilities and D-Equipment]. The specifications, drawing, checklists and other data that support the physical equipment (hardware) utilized for the process.
4 Calibration [21 CFR 211 Subparts D – Equipment]. The methods and controls that establish the accuracy of data.
5 Analytical Methods [21CFR 211 Subparts I – Laboratory Controls]. The means to evaluate the outcome of the process on the materials.
6 Cleaning – [21 CFR 211.67Equipment Cleaning and Maintenance]. A specialized process, the intent of which is to remove the traces of the prior product from the equipment.
7 Change Control – [21 CFR 211. 100(b) Equipment Cleaning and Maintenance]. A formalized process control scheme that evaluates changes to documentation, materials, and equipment.
The pharmaceutical industry participated in the introduction of computers into the manufacturing environment during the 1980s. This led to FDA concerns relative to the validation of computerized system used within the industry. The pharmaceutical industry‘s response to the FDA‘s new concerns regarding validation of computerized systems was somewhat different than what had occurred previously. The Pharmaceutical Manufacturers Association established an interdisciplinary group called the Computer Systems Validation Committee (CSVC) in late 1983 to address how the industry would address the FDA‘s concerns. Through the creation of the
13 CSVC, the industry began to assume a position of leadership regarding validation. Through the auspices of the CSVC, an industry approach to the validation of computerized systems in the GMP environment was established.9 Central to the industry position, was the adoption of the ―life cycle‖ concept as an appropriate model for managing the activities needed for the successful validation of computerized systems (Figure 1). The life cycle approach focuses on managing a project from cradle to grave. When employing the life cycle approach, the design, implementation, and operation of system (or project) are recognized as interdependent parts of the whole. Operation and maintenance concerns are addressed during the design of the system and confirmed in the implementation phase to ensure their acceptability. The adoption of the life cycle methodology afforded such a degree of control over the complex tasks associated with the validation of computerized systems that it came into nearly universal application within a very short period.
Figure 1
1.3 Why validation?
First and foremost, among the reasons for validation is that it is a regulatory requirement for virtually every process in the global healthcare industry – for pharmaceuticals, biologics, and medical devices. Regulatory agencies across the world expect firms to validate their processes. The continuing trend toward harmonization of requirements will eventually result in a common level of expectation for validations worldwide.
Number of tangible and intangible benefits of validation was realized (Table 2)10. In the intervening years, there has been repeated affirmation of those expectations at other firms, large
14 and small. Regrettably, there has been little quantification of these benefits. The predominance of compliance-based validation initiatives generally restricts objective discussion of cost implications for any initiative. But once a process/product is properly validated, it seem that reduced sample size and intervals could be easily justified, and thus provide a measurable return on the validation effort. Aside from utility systems, it is hardly ever realized and represents one of the major failings relative to the implementation of validation in pharmaceutical industry.
Table 1: Benefits of Validation Increased throughput
Reduction in rejections and reworks Reduction in utility costs
Avoidance of capital expenditures
Fewer complaints about process related failures Reduced testing in process and finished goods
More rapid and accurate investigations into process deviations More rapid and reliable startup of new equipment
Easier scale-up from development work Easier maintenance of the equipment Improved employee awareness of processes More rapid automation
Validation and validation-like activities are found in a number of industries, regulated and unregulated. Banking, aviation, software, microelectronics, nuclear power, among others all incorporate practices closely resembling validation of health care product production. The health care industries fixation on compliance has perhaps blinded us the real value of validation practices.
1.4 What has to be validated?
Validation efforts in the analytical laboratory should be broken down into separate components addressing the equipment (both the instrument and the computer controlling it) and the analytical methods run on that equipment. After these have been verified separately they should be checked together to confirm expected performance limits (so-called system suitability testing), and finally
15 the sample analysis data collected on such a system should be authenticated with suitable validation checkouts. Other activities include checking reference standards and qualification of people.
1) Equipment: All (computerized) equipment that is used to create, modify, maintain, archive, retrieve, or distribute critical data for cGMP/GCP/GLP purposes should be validated. Validation of hardware includes testing the instrument according to the documented specifications. Even though this may include word processing systems to create and maintain SOPs, it covers analytic systems only. If instruments consist of several modules, a modular HPLC system for example, the entire system should be validated. Validation of computer systems must include the qualification of hardware and software.
2) Analysis method: Validation covers testing of significant method characteristics, for e.g sensitivity and reproducibility.
3) Analytical system: The system combines instrument, computer and analytical method. This validation usually referred to as system suitability testing, tests the system for documented performance specifications for the specific analysis method.
4) Data: When analyzing samples the data must be validated. The validation process includes documentation and checks for data plausibility, consistency, integrity, and traceability. A complete audit trail must be in place, which allows tracing back the final result to the raw data for integrity.
5) Personnel: People should be qualified for their jobs. This includes education, training and/or experience.
6) Reference standards: Reference standard should be checked for purity, identity, concentrations and stability.11
1.5 Scopes of Validation
There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved.
16 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed.
There should be proper preparation and planning before validation is performed. There should be a specific programme for validation activities.
Validation should be performed in a structured way according to the documented procedures and protocols.
Validation should be performed for:
For new premises, equipment, utilities and systems, and processes and procedures. At periodic intervals, and
When major changes have been made.
(Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required).
Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced.
Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered.
There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously.
When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality.
Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A
17 risk assessment approach should be used to determine the scope and extent of validation required.12
1.6 Pre-Requisites for Successful Validation
There are some elements or tools that are required for conducting effective validations. Each are presented and discussed in the following sections:
Understanding
The single most important element required is a good understanding of what validation is. This understanding activity goes beyond the basic definition of validation, beyond the concept of ―requiring a minimum of three runs‖ and understanding must be anchored by sufficient years of practical experience and knowledge. It will permit sound and logical decisions even under most intense situations.13
Communication
Communication is one of the best methods of improving environment understanding. It is essential for any activity that requires more than one resource to complete. This point is understandable considering that conducting effective validation involves multi-departments. Co-operation and Focus
Multi departments that sometimes interact during the course of executing validation program are project management, accounting, quality control, project engineering, process engineering, quality assurance, facilities; regulatory etc should have a commendable co-operation.
Experience
A firm must have resources with solid validation experience to get success in their validation program.
Resources
Resources mean personnel who will plan and execute equipment on which validations will be performed on materials with which to conduct validations. Laboratories that will perform necessary analysis should provide necessary funding for the validations and allocate sufficient time to perform validations.14
Plan
Conducting validations within most companies will involve a number of departments and disciplines. These disciplines need a perfect plan in order to get good team synergy.
18 Budget
It is important to understand that a successful validation must be done to completion and it should not be limited by a budget assembled by personnel who have no appreciation for what is required to successfully complete validation. Further, it is important to understand that validations cost money.15
Standard Operating Procedures (SOPs)
The SOPs capture activities that routinely occur within an organization. Departments charged with abiding by or following these SOPs must first be trained against these SOPs.
Quality Control lab support
In most of the validations, some laboratory testing will be required. In most cases this testing is handled by the QC group. QC is expected to provide results in timely manner. So often, the wait for the receipt of analytical results cases the entire validation project to come to halt. Because validations are based on the results obtained.
1.7 Approaches of Validation
According to the WHO, there are two basic approaches to validation; one is based on evidence obtained through testing (prospective and concurrent validation), and another is based on the analysis of accumulated (historical) data (i.e. retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products.
Both prospective and concurrent validation may include following:
Extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity.
Simulation process trials
Challenge/ worst case tests, which determine the robustness of the process, and
Control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.16
1.8 Phases in Validation17:
The activities relating to validation studies may be classified into three phases mainly. They are as follows:
19 1. Pre-validation Qualification Phase: It covers all activities related to product research and development, formulating pilot batch studies, scale-up studies, technology transfer to commercial scale batches, establishing stability conditions and storage, and handling of in-process and finished dosage forms, equipment; operational and installation qualification, master production document and process capacity.
2. Process validation phase: It is designed to verify that all established limits of the critical process parameters are valid and satisfactory products can be produced even under worst conditions.
3. Validation Maintenance phase: It requires frequent review of all process related documents, including audit reports, to assure that there have been no changes, deviations, failures and modifications to the production process and that all SOPs, including change control procedures have been followed. At this phase, the validation comprising of members from all major departments assures that there have been no changes/deviations that should be resulted in requalification and revalidation. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots of batches produced will meet their intended specifications. Thus, it‘s assumed that throughout manufacturing and control, operations are conducted in accordance with the principle of GMP both in general and in specific reference to sterile product manufacture.
The validation steps recommended in GMP guidelines can be summarized as follows18:
As a requisite, all studies should be conducted in accordance with a detailed, pre-established protocol or series of protocols, which in turn is subject to formal – change control procedures.
Both the personnel conducting the studies and those running the process being studied should be appropriately trained and qualified and be suitable and competent to perform the task assigned to them.
All data generated during the course of studies should be formally reviewed and certified as evaluated against pre-determined criteria.
Suitable testing facilities, equipment, instruments and methodology should be available. Suitable clean room facilities should be available in both the ‗local‘ and background
environment. There should be assurance that the clean room environment as specified is secured through initial commissioning (qualification) and subsequently through the
20 implementation of a programme of re-testing – in-process equipment should be properly installed, qualified and maintained.
When appropriate attention is paid to above, the process, if aseptic, may be validated by means of ―process simulation‖ studies.
The process should be revalidated at specific time intervals.
Comprehensive documentation should be available to define support and record the overall validation process.
1.9 Validation Decision Tree:
This model describes a decision tree that helps manufacturer decide on whether processes need to be validated or not. It is one of the easiest models under consideration.
Each process should have a specification describing both the process parameters and the desired output. The tree is described below:
A Is process Output Verifiable B Is Verification Sufficient & Cost Effective C Verify & Control the Process D Validate E Redesign Product and/or Process NO NO Yes YES
21 A. The manufacturer should consider whether the output can be verified by subsequent
monitoring or measurement.
B. If the answer is positive, then the consideration should be made as to whether or not verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution. C. If yes, the output should be verified and the process should be appropriately controlled. D. If the output of the process is not verifiable then the decision should be to validate the
process.
E. The product or process should be redesigned to reduce variation, improve product or process and decrease risk or cost to a point where verification is acceptable decision.
22
2. Organizing for Validation
Validation and its role within a pharmaceutical organization have come a long way from its inception in the 1970s, when the effort was primarily focused on sterilization validation and demonstrating that the conditions to achieve sterility were met. As a result, it was managed from within the sterile manufacturing unit using a small team. In the 1980s, validations organizations were created and began interacting with other groups such as Research, Engineering, Production, Manufacturing, and Quality Assurance.
Formulating a mission is essential to ensure proper definition of a department role in the formation. Although there is broad diversity of validation department missions within the pharmaceutical industry, the mission that is general to all validation departments is the satisfying of the regulatory requirement to have processes validated. Certainly the validation mission is influenced by the size of the company as well as its product lines.
2.1 Staffing issues
When staffing a validation group, the mission and the organization exert a degree of influence, primarily in the academic backgrounds of the members. Because of the aforementioned diversity, a considerable variety of academic backgrounds are usually found among validation professionals, such as members having degrees in chemistry, microbiology, pharmacy, statistics, computer science, biochemistry as well as engineering disciplines. For e.g. when the mission is directed toward a sterile products focus, having a microbiology degree would be beneficial. In general sense, the more important than the actual academic background are these 3 skills: problem-solving capability, interpersonal skills, and oral and written communication abilities. The technical talent to recognize and solve problems is fundamental to validation. Finally, it is targeted that the validation members be able to effectively express the validation objectives and concerns both orally and in written form. If the professional can successfully communicate orally, esp. during an FDA visit, the strength of validation package is expected to be even greater.
2.2 Department interactions
Once missions of departments have been formalized and the validation operations are organized, the main challenge is to implement the plan, which requires interaction with many peer groups. Within the company, other departments involved in validation taskforce are as follows:
23 1. R & D: It is involved with new product and process development and often existing process improvements. Their key responsibility in validation is to ensure the acceptability (and thus validatability) of new products or ―improved‖ process in the manufacturing area. They must be aware of the validation plan and resulting acceptance criteria.
2. Engineering: It is involved with new or modified equipment or facilities and their start-ups. Their role is to ensure the acceptability of the processes later on, so their concern must be built in at the design phase and continued through construction.
3. Production: It is concerned with processes that require validation and stress the benefits of a validation program.
4. Maintenance: It‘s concerned with change control, calibration, and preventative maintenance. This occurs at the instant when an undocumented change is made to a validated piece of equipment.
5. Quality Control: It‘s involved with the testing laboratories and ensures that laboratory personnel know not only the number and type of tests required for the study but also how the testing fits into the overall validation program.
6. Quality Assurance: It‘s concerned with GMP compliance to ensure a firm‘s regulatory compliance. Through the technical competency of the validation staff and the GMP compliance expertise existing within the QA group, these efforts should be successful. The key point is to communicate so that the regulatory compliance objective of validation is met. Whether the process is a bulk process or one of the finishing steps; whether it is a proprietary purification process, a steam sterilization process, or a conventional non-sterile process; whether the focus is a clinical manufacturing lot or commercial production; or whether the effort is accomplished within the firm, contracted out in conjunction with an outsourced manufacturing agreement, or with the assistance of a consultant, the validation staff must possess 4 things:
i. Technical expertise, allowing a thorough understanding of the process being reviewed. ii. Understanding of the fundamentals of validation and the ability to apply them to the process. iii. Interpersonal skills necessary to deal with all of the organizations within and outside of the
firm.
iv. Support from management, which positions the validation effort as a critical element in the company‘s success.
24 2.3 Master planning or planning for Validation
The validation master plan (VMP) has become common practice for all large capital projects within the global healthcare industry. The master plan has come into vogue to ensure that the validation requirements for major facilities are adequately addressed. Although it‘s often described as a regulatory requirement, there is in fact no such requirement in any of the world‘s cGMP regulations; nevertheless, its real value is as a management tool to be used to coordinate the validation effort. It is an indispensable tool that delineates how the validation effort is to be executed. The utility of plan diminishes with facility size and complexity, but even small projects may benefit from the structure that a master plan brings to the validation effort.20
VMP is a good practice to document all validation activities in a document. The FDA does not specifically demand a validation master plan however; inspectors want to know what the company‘s approach towards validation is. So, VMP is an ideal tool to communicate this approach internally and to inspectors.21 The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the VMP. It should comprise all prospective, concurrent and retrospective validations as well as revalidation.22 The VMP should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following:
A validation policy
Organizational structure of validation activities
Summary of facilities, systems, equipment and processes validated and to be validated. Documentation format (e.g. protocol and report format)
Planning and scheduling Change control
References to existing documents 2.4 Benefits of Master Planning
Numerous benefits are derived from a VMP which can substantially enhance the firm‘s validation posture for the project. A well-structured plan will provide following advantages to a firm:
25 i. Codify decisions regarding how cGMP requirements will be satisfied.
ii. Allow detailed definition of validation activities necessary for the successful operation of the facility.
iii. Serve as an important document in regulatory compliance and interaction. iv. Serve as a communication document on the validation for use with third parties.
v. Be easily converted into a Drug Master File
vi. Serve as an excellent tool for audit preparation (either internal or external). vii. Define project execution through the definition of requirements.
viii. Help determine resource needs for personnel, materials, equipment, components and laboratory analysis.
ix. Ease protocol and report preparation through the definition of accepted formats. x. Be used as a bid document when soliciting bids for contract execution.
2.5 Validation Process
Each part of the validation process should be documented. There should be a written plan for performing each validation to specify who is responsible for managing and performing the various validation tasks such as production of validation protocols and approvals of validation documentation. Validation protocols should be written for each phase of the validation to include acceptance criteria. The validation plan and the validation protocols may be combined into a single document. The outcome of each phase of validation should be recorded and the overall conclusions, with a scientific assessment of any failures should be documented in a validation summary report. The validation records and summary report must be reviewed and approved before putting the process or system affected into use.
2.6 Validation Plan
The plan should first identify the following things: What is being validated
Where the validation will take place
Why the validation is taking place providing reference to any relevant change control records, risk assessments, URS and FDS.
26 Validation time-frames
The plan should also identify the validation team and define responsibilities for : Overall management of the validation
Production of protocols
Performing the validation and recording the outcome
Reviewing and approving the protocols and validation records
Reviewing the validation outcomes and signing off the validation as acceptable.23
2.7 Typical validation master plan structure
There is no standard format for master plans. Various authors used different types of plans with appropriate adaptations to suit to specific requirements of a particular project. The most successfully used plan‘s basic template is given in table below (table 3)24
. It can be readily modified to different project types and scales. With changes in the facility type, there is a corresponding change in the focus of the master plan.
Table 3 – Validation master plan template
Introduction Introduction to the project scope, location, and timing. Includes responsibilities for protocol, SOP, report and other documentation preparation and approval. Identifies who is responsible for the various activities. A general validation SOP or policy statement may be included.
Plant/Process/Product Development
A concise description of the entire project is provided. It will provide information on layout and flow of personnel, materials, and components; utility and support systems; description of the processes to be performed and products to be made in the facility. Major equipment is also described.
Computerized System and Process Control Description (If needed)
Computerized information, laboratory and process control systems are described in sufficient detail to delineate the validation requirements. This section may be omitted if the level of automation is minimal.
27 List of Systems/
Processes/Products to be validated
Equipment, systems, and products are listed in a matrix format that describes the extent of validation required (i.e. IQ, OQ, or PQ) as part of the project. Additional breakout of computerized, cleaning and sterilization validation requirements can be added.
General and Specific Acceptance Criteria
Key acceptance criteria (general and specific) for the items listed in the prior section are provided. Emphasis should be placed on quantitative criteria throughout. To merely state the general requirements provides no substantial benefit to either those responsible for the validation or for those involved in the design process.
Special Issues (if needed)
Sections can be included describing in greater detail the validation requirements of an element of the project where additional clarification may be warranted. Typical subjects include automation, cleaning, containment, isolation, or lyophilization.
Protocol and
Documentation format
The format to be used for protocols, reports, and operating procedures is described. This particularly useful in a new organization where such formats have not yet been defined. It can also be beneficial when working with an outside contractor to ensure that all documentation is in the correct format.
Required procedures List of SOP‘s (new or existing) necessary to operate the facility.
Manpower planning and scheduling
An estimate of the staffing requirements to complete the validation effort described in the plan. A preliminary schedule of required activities is prepared to help estimate appropriate manning levels.
2.8 Validation Protocol
Validation protocol is the step that comes after validation plan. It is an integral element of the validation plan. The protocol describes:
28 The tests that will be performed
The test procedures
The objectives of the validation in terms of acceptance criteria for each test Records to be completed.
What needs to be tested, how many tests to do and the acceptance criteria at each validation phase will be specific to each validation and must be founded on the scientific and technical basis of the processes and systems involved. It should be possible to establish the specific requirements by reference to the relevant risk assessments, URS, FDS, published standards, regulations & guidelines.25
The detailed protocols for performing validations are essential to ensure that the process is adequately validated. It should include the following elements:
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.
Process variables and attributes with probable risk and prevention shall be captured. 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.
29 There should also be a description of the way in which the results will be analyzed. The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change. The validation protocol and report may also include copies of the product stability report or a summary of it, validation documentation on cleaning, and analytical methods.
2.9 Validation set up
Validation set up is very essential to establish the desired attributes. These attributes include physical as well as chemical characteristics. In the case of parenterals, these attributes should include stability, absence of pyrogens, and freedom from visible particles.
Acceptance specifications for the product should be established in order to attain uniformity and consistently the desired product attributes, and the specifications should be derived from testing and challenge of the system on sound statistical basis during the initial development and production phases and continuing through subsequent routine production.
The process and equipment should be selected to achieve the product specification. For e.g. design engineers; production and quality assurance people may all be involved. The process should be defined with a great deal of specificity and each step of the process should be challenged to determine its adequacy. These aspects are important in order to assure products of uniform quality, purity and performance.26
2.10 Relationship between validation and qualification
Validation and qualification are essential components of the same concept. The term qualification is normally used for equipment, utilities and systems, and validation for processes. In this sense, qualification is part of validation. Qualification is pre-requisite of validation. There are four phases/stages of qualification for process, equipment, facilities or systems:
Design qualification (DQ); Installation qualification (IQ) Operational qualification (OQ) Performance qualification (PQ)
30 All SOPs for operation, maintenance and calibration should be prepared during qualification. Training should also be provided to operators and training records be maintained.
2.10.1 Design Qualification (DQ)
DQ is defined as ―Providing documented verification that all key aspects of the design, procurement and installation adhere to the approved design intention and that all the manufacturers’ recommendations have been suitably considered.”27
It defines the functional and operational specifications of the instrument and details the conscious decisions in the selection of the supplier.28 DQ covers all aspects of the design and procurement of facility and equipment. It is intended to encompass all those activities that might take place in the design phase, detailed and development, including activities associated with procurement of equipment and checkout at the supplier‘s works. It is a verification that the design meets user requirements with a particular focus on those requirements that relate to GMP and product quality. The extent of DQ may depend on the contract arrangements. Design may be subcontracted to suppliers or subcontractors and how this is covered should be defined in the plan. DQ is not a regulatory requirement but a smart activity to include in the qualification process. It is essential that aspects of design are demonstrated in the qualification process as the existing regulations require that facility and equipment are of suitable design and appropriate to purpose.
DQ should also provide documented evidence that the design specifications were met. Any validation should start with setting and documenting the specifications for user requirements, instrument functions and performance. The specifications of the instrument‘s design should be compared with the user requirement specifications. It is a simple rule of thumb: without specifications there is no validation. DQ is the most important step in the validation process. Errors made in this phase can have a tremendous impact on the workload during later phases. Steps for design qualification: The recommended steps that should be considered for inclusion in a design qualification are listed below:
Description of the analysis problem. Selection of the analysis technique.
Description of the intended use of the equipment.
Preliminary selection of functional and performance or operational specifications (technical, environmental, safety).
31 Preliminary selection of the supplier.
Instrument tests (if the technique is new). Final selection of the equipment.
Final selection of the supplier.
Development and documentation of the final functional and operational specifications. Role of vendor for design qualification
Although the user of a system has ultimate responsibility for validation, the vendor also plays a major role. The validation covers the complete life of a product, starting with the design and development. For commercial off the shelf systems, the user has hardly any influence on how the software is being developed and validated, but he can check through documentation to see if the vendor followed in acknowledged quality process.
Tasks of the vendor: The vendor should
Develop and validate software following documented procedures.
Test the system and document test cases, acceptance criteria and test results. Retain the tests protocols and source code for review at the vendor‘s site. Provide procedures for IQ and OQ/PV.
Implement a customer feedback, change control and response system. Provide fast telephone, e-mail and/ or on-site support.
Qualification of the vendor
As a part of the qualification process, the vendor should be qualified. The question is, how should this be done? Is an established and documented quality system enough, for e.g. ISO 9001? Should there be a direct audit? Is there another alternative between these two extremes? There may be situations where a vendor audit is recommended: for e.g. when computer systems are being developed for a specific user. However, this is rarely the case for analytical equipment. Typically, off-the-shelf systems are purchased from a vendor with little or no customization for specific users.
The exact procedure to qualify a vendor depends very much on the individual situation, for e.g. is the system in mind employing mature or new technology? Is the specific system in widespread use either within your own laboratory or your company, or are there references in the same industry? Does the system include complex computer hardware and software?
32 2.10.2 Installation Qualification (IQ)
It can be defined as ―process of obtaining and documenting evidence that equipment has been provided and installed in accordance with the specification.‖ IQ establishes that the instrument is received as designed and specified, that it is properly installed in the selected environment, and that this environment is suitable for the operation and use of the instrument. This involves verification of good engineering practice in installation of equipment, and should consider electrical safety, safety issues, location siting, and maintenance/calibration schedules and should confirm that the installation has been carried out as specified with the appropriate supporting documentation. This activity can be delegated to the supplier, provided that the content of the IQ document is approved in advance by the laboratory.
IQ should provide documented evidence that the installation was complete and satisfactory. It should also clearly define those areas and items of equipment systems that are to be qualified. The purpose specifications, drawings, manuals, spare parts lists and vendor details should be verified during installation qualification. Also, control and measuring devices be calibrated. Steps for IQ: Steps for IQ include activities prior and during installation of the equipment. The recommended steps are as follows:
a) Before installation
Obtain manufacturer‘s recommendations for installation site requirements.
Check the site for the fulfillment of the manufacturer‘s recommendations (utilities such as electricity, water and gases and environmental conditions such as humidity, temperature and dust).
Allow sufficient shelf space for the equipment, SOPs, operating manuals and software. b) During installation
Compare equipment, as received, with purchase order (including software, accessories, spare parts)
Check documentation for completeness (operating manuals, maintenance instructions, and standard operating procedures or testing, safety and validation certificates).
Check equipment for any damage.
Install hardware (computer, equipment, fittings and tubings for fluid and gas connections columns in HPLC and GC, power cables, data flow and instrument control cables).
33 Switch on the instruments and ensure that all modules power up and perform an
electronic self-test.
List equipment manuals and SOPs. Prepare an installation report. 2.10.3 Operational Qualification (OQ)
It can be defined as ―process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures.” OQ is the process of demonstrating that an instrument will function according to its operational specification in the selected environment. It should provide documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications. Tests should be designed to demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions). Operation controls, alarms, switches, displays and other operational components should be tested and measurements made in accordance with a statistical approach should be fully described.29 It should prove that the instrument is suitable for its intended use. It is not required to prove that the instrument meets the manufacturer‘s performance specifications. Frequently, people misunderstand and prefer to use the manufacturer‘s specifications because usually these are readily available.
Moreover, this is the verification of process, equipment and facilities over its operating range and is assessed against the specifications as defined in the URS. During this stage, a range of tests will be carried out to demonstrate the integrity and functionality of the system, including the ability to operate under worst case conditions. Confirmation that all calibration, operating and cleaning processes have been defined and tested will be required. Definition of the required programme of planned preventative maintenance (PPM) should be considered. It can be carried out by the supplier and/or by laboratory, or a combination of both. In any case, this must be performed using and agreed OQ protocol.
Steps for OQ
34 Define test cases and acceptance criteria. For an HPLC system such tests include precision of retention times and peak areas, wavelength accuracy of UV detectors, gradient accuracy and precision, system carry over, baseline noise and detector linearity.
Perform tests and compare the results with the acceptance criteria. 2.10.4 Performance Qualification (PQ)
It is defined as ―process of obtaining and documenting evidence that the equipment, as installed and operated in accordance with operational procedures, consistently performs in accordance with predetermined criteria and thereby yields product meeting its specifications.” Successful completion of IQ and OQ is followed by PQ. It can also be defined as documented verification that all aspects of a facility, utility or equipment perform as intended in meeting predetermined acceptance criteria. This is performed to demonstrate that the process, equipment or facility performs as required under routine operational conditions and as defined in the URS. This is sometimes referred to as Process validation and is the stage of the exercise when the equipment or process is assessed in its practical application, with operational outputs/product being assessed for acceptability.30 It should provide documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use.
This is generally applicable to those systems that require extended testing over a period of time such as water systems, heating, and ventilation systems such as those applicable to clean rooms and the actual performance of the clean room to meet the defined standards of operation over periods of time. Some organizations may include PQ in the OQ.
PQ should include following, however, it is not exclusive.
Tests using production materials, substitutes or simulated product.
Tests to include condition(s) with upper and lower limits. It will be useful to briefly discuss process capability design and testing and process qualification.
Check actual product and process parameters and procedures established in OQ. Test acceptability of the product.
35 2.10.5 Component Qualification (CQ)
It is relatively new term developed in 2005. This refers to the manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. This could involve packaging components such as folding cartons, shipping cases, labels or even phase change material. All of these components must have some type of random inspection to ensure that the third party manufacturer‘s process is consistently producing components that are used in the world of GMP at drug or biologic manufacturer.31
2.10.6 Requalification
Requalification should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. There should be periodic requalification, as well as requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement). It should be considered as part of the change control procedure.
2.10.7 Revalidation
Revalidation can be defined as repeating the original validation effort or any part of it, which includes investigative review of existing data. It is essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems. Processes and procedures should be revalidated to ensure that they remain capable of achieving the intended results. There should be periodic revalidation, as well as revalidation after changes. It should be done in accordance with a defined schedule. The frequency and extent of revalidation should be determined using a risk based approach together with a review of historical data.
Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment. The following should be considered when periodic revalidation is performed:
Master formulae and specifications SOPs
Records (e.g. of calibration, maintenance and cleaning) Analytical methods
