A Reveiw on Pharmaceutical Validation

Contents Glossary: ....................................................................................................................................................... 5 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

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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 2.10.8 Revalidation after change......................................................................................................... 36

A REVIEW ON PHARMACEUTICAL VALIDATION 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 3.4.5 Software validation .................................................................................................................... 90 2

A REVIEW ON PHARMACEUTICAL VALIDATION 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 3.9.5 Operating Procedure and Training ........................................................................................... 132 3

A REVIEW ON PHARMACEUTICAL VALIDATION 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

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A REVIEW ON PHARMACEUTICAL VALIDATION

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 5

A REVIEW ON PHARMACEUTICAL VALIDATION 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.

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A REVIEW ON PHARMACEUTICAL VALIDATION 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 nonfunctional 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. 27. Specification – It is a document that states requirements.

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A REVIEW ON PHARMACEUTICAL VALIDATION 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.

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A REVIEW ON PHARMACEUTICAL VALIDATION

1. Introduction to validation 1.1 Definition Validation 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) 9

A REVIEW ON PHARMACEUTICAL VALIDATION 

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 10

A REVIEW ON PHARMACEUTICAL VALIDATION 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 predetermined 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.

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A REVIEW ON PHARMACEUTICAL VALIDATION 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 JRecords 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 DEquipment]. 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 12

A REVIEW ON PHARMACEUTICAL VALIDATION 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 13

A REVIEW ON PHARMACEUTICAL VALIDATION 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 14

A REVIEW ON PHARMACEUTICAL VALIDATION 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.

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A REVIEW ON PHARMACEUTICAL VALIDATION 

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

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A REVIEW ON PHARMACEUTICAL VALIDATION 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 cooperation.



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. 17

A REVIEW ON PHARMACEUTICAL VALIDATION 

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: 18

A REVIEW ON PHARMACEUTICAL VALIDATION 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 inprocess 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 pre-requisite, all studies should be conducted in accordance with a detailed, preestablished 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 19

A REVIEW ON PHARMACEUTICAL VALIDATION 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. A Is process Output Verifiable

YES

B Is Verification Sufficient & Cost Effective

Yes

C Verify & Control the Process

NO

NO

E Redesign Product and/or Process

D Validate

Figure- 2: Validation Decision Tree

Each process should have a specification describing both the process parameters and the desired output. The tree is described below:

20

A REVIEW ON PHARMACEUTICAL VALIDATION 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.

21

A REVIEW ON PHARMACEUTICAL VALIDATION

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:

22

A REVIEW ON PHARMACEUTICAL VALIDATION 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. These basics ensure that the validation effort is successfully accomplished.19 23

A REVIEW ON PHARMACEUTICAL VALIDATION

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: 24

A REVIEW ON PHARMACEUTICAL VALIDATION 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.



The validation stages required 25

A REVIEW ON PHARMACEUTICAL VALIDATION 

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

A concise description of the entire project is provided. It will

Development

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

Computerized information, laboratory and process control systems

and Process Control

are described in sufficient detail to delineate the validation

Description (If needed)

requirements. This section may be omitted if the level of automation is minimal. 26

A REVIEW ON PHARMACEUTICAL VALIDATION List of Systems/

Equipment, systems, and products are listed in a matrix format that

Processes/Products to

describes the extent of validation required (i.e. IQ, OQ, or PQ) as

be validated

part of the project. Additional breakout of computerized, cleaning and sterilization validation requirements can be added.

General and Specific

Key acceptance criteria (general and specific) for the items listed in

Acceptance Criteria

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

Sections can be included describing in greater detail the validation

needed)

requirements of an element of the project where additional clarification may be warranted. Typical subjects include automation, cleaning, containment, isolation, or lyophilization.

Protocol and

The format to be used for protocols, reports, and operating

Documentation format

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

An estimate of the staffing requirements to complete the validation

and scheduling

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: 

The qualification/validation phase (IQ,OQ, PQ or method process validation) 27

A REVIEW ON PHARMACEUTICAL VALIDATION 

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.

28

A REVIEW ON PHARMACEUTICAL VALIDATION 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)



Component qualification (CQ), only sometimes stated.

29

A REVIEW ON PHARMACEUTICAL VALIDATION 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). 30

A REVIEW ON PHARMACEUTICAL VALIDATION 

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?

31

A REVIEW ON PHARMACEUTICAL VALIDATION 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).

32

A REVIEW ON PHARMACEUTICAL VALIDATION  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 

Define intended functions to be tested.

33

A REVIEW ON PHARMACEUTICAL VALIDATION 

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.



Check process repeatability, and long term process stability.

34

A REVIEW ON PHARMACEUTICAL VALIDATION 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

35

A REVIEW ON PHARMACEUTICAL VALIDATION 2.10.8 Revalidation after change Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure. The extent of revalidation will depend on the nature and significance of the changes. Changes should not adversely affect product quality or process characteristics. The changes requiring revalidation should be defined in the validation plan, and it may include following: 

Changes in starting materials (including physical properties, such as density, viscosity or particle size distribution that may affect the process or product)



Change of starting material manufacturer



Transfer of processes to a different site (including change of facilities and installations which influence the process)



Changes of primary packaging material (e.g. substituting plastic for glass)



Changes in the manufacturing process (e.g. mixing times or drying temperatures)



Changes in the equipment (e.g. addition of automatic detection systems, installation of new equipment, major revisions to machinery or apparatus and breakdowns);



Production area and support system changes (e.g. rearrangement of areas, or a new water treatment method)



Appearance of negative quality trends



Appearance of new findings based on current knowledge, e.g. new technology



Support system changes.

Changes of equipment which involve the replacement of equipment on a ―like-for-like‖ basis would not normally require revalidation. For e.g. installation of a new centrifugal pump to replace an older model would not necessarily require revalidation.32

2.10.9 Change Control Process capability design, testing and process qualification Process capability can be defined as the study of critical parameters/operating variables that influence process output and the range of data for each of the critical process parameters that will result in acceptable process output. The objectives of process capability design and testing are:

36

A REVIEW ON PHARMACEUTICAL VALIDATION 

Determination of number of critical parameters in a process that affect the quality of process output and their relative importance,



To show that the generated numerical data for each critical parameter are within atleast statistical quality control limits (i.e. ±3standard deviations) and that there is no assignable cause of variation in the process data.

Process qualification is the study of trials conducted to show that all systems/subsystems or unit manufacturing operations perform as intended that all critical process parameters remain within assigned control limits; and that such studies and trials are verifiable and certifiable through documentation. Process qualification is also referred to as operational or performance qualification. Such studies or trials form the basis of process capability design and testing.33

2.11 Documentation It is essential that the validation program is documented and is properly maintained. So a written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria.34 Each stage of the validation process should be fully documented, reviewed, authorized and ―signed off‖. There should be a formal review of each stage of validation and documented approval before proceeding to the next stage. The reports should reflect the protocols followed and include atleast the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods. The results should be evaluated, analyzed and compared against the pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-limit results should be investigated. If these deviations are accepted, this should be justified and where necessary further studies should be performed. Usually, the department responsible for the qualification and validation work should approve the completed work. And the conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful. The quality assurance department approves the report after the final review. The criteria for approval should be in accordance with the company‘s quality assurance system. Any deviations found during the validation process should be acted upon and documented as such and corrective actions be taken, where required. 35

37

A REVIEW ON PHARMACEUTICAL VALIDATION Usually, a report that cross-references the qualification and/or validation protocol is prepared summarizing the results obtained, commenting on any deviations observed, and drawing necessary conclusions, including recommending changes necessary to correct deficiencies. For e.g. in routine production, it is important to adequately record process details (e.g. time, speed, temperature, & equipment used) and any changes which have record. A maintenance log is also maintained, which is useful in performing failure investigations concerning a specific manufacturing lot. The document (i.e. validation report) on completion of the installation and operation qualification consists of: 

Validation plan and protocols.



User requirement and functional specifications.



Evidence of vendor qualification.



The IQ document (includes description of hardware and software).



Operating and maintenance manuals and SOPs for testing.



Qualification test reports with signatures and dates.



Summary of test results and a formal statement that the system has been accepted.



Approval of user, validation department and quality assurance.36

The samples of check-lists for different qualifications are given below:

38

A REVIEW ON PHARMACEUTICAL VALIDATION

Installation Qualification (IQ) Name of company: The White Horse Pharmaceuticals Address: Raj-fulbaria, Savar, Dhaka. Check list for installation Qualification for: HPLC Qualification Protocol No:………WHP: 002

Date:10-11-2013

Has the equipment been delivered according to purchase order?

Yes

√

No

Has the equipment been checked for damage (Equipment should be undamaged).

√

Yes

No

Has the required documentation been supplied? Is it of correct issue and identified properly by model number, serial number and date?

√

Yes

No.

Yes

No.

Have details of all the services and utilities required to operate equipment been provided?

√

Have methods and instructions for maintenance been provided along with spare parts and contact points for service?

√

Yes

No.

Is the selected environment suitable for the equipment? Have appropriate utilities (e.g. electricity, gas, steam, water, etc.) been provided?

√

Yes

No.

Has information regarding health, safety and environment in relation to the operation of the equipment been provided?

√

Yes

No.

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A REVIEW ON PHARMACEUTICAL VALIDATION

Signature:

Signature:

Name of the person:

Name of the person:

Designation:

Designation:

Date:

Date:

(On the behalf of manufacturer of

(On the behalf the company)

equipment) In case of OQ and PQ, qualification protocol has to be prepared which will include: 

SOP for OQ and PQ



References to SOPs for: o Calibration of measuring devices, if the equipment has them o Operator‘s training; o Preventive maintenance; o Cleaning and sanitization;



Formats for documentation and certification.

{Formats suggested below are based on WHO publication. A WHO guide to Good Manufacturing Practice (GMP) requirements Part 2; Validation.}

40

A REVIEW ON PHARMACEUTICAL VALIDATION

Operational Qualification (OQ)

Name and address of Company: The White Horse Pharmaceuticals Validation Protocol No: WHP 006 Operational Qualification: Name of Equipment /System: Mass Mixture A. Materials, Equipment‘s, Documents: 

List of Calibration equipment required.



Materials and Supplies needed to perform OQ.



SOPs and Data Sheets for normal operation of equipment/System.



Records of training of operators.



Manuals‘ for equipment.

B. Procedure: 

Test and record calibration data for such instruments which need calibration.



Test and record operation conditions of control points and alarms (e.g. temp., rotation, velocity, etc.).



Test and record output.



Measure and record the results of Challenge to the system in normal and worst case situation where required.



Following: o Record any deviations to the procedure, if made. o Prepare a deviation report giving justification of acceptance of deviation and its impact on operation. o Report. 

Prepare a report on OQ.



Submit to QA for review and approval.37

41

A REVIEW ON PHARMACEUTICAL VALIDATION

Performance Qualification (PQ)

Name and Address of Company: Validation Protocol No: Performance Qualification: A. Materials, Equipment‘s, Documents: 

List of Materials.



List of equipment.



List of SOPs

(SOPs which are specific to the performance tests including data sheets, charts predetermined specifications and acceptance limits) B. Procedure: 

Equipment‘s: Run three times employing normal procedure for each uses (configuration or load) and records the data on data sheet. Also record deviation to the procedure, if made.



System: Run for 20 consecutive working days and record data on datasheet. Also record deviation to procedure, if made. (Prepare summary of the data).

C. Evaluation: 

Perform required calculation and statistical analyses,



Compare the results with acceptance limits.



If there has been deviation to the procedure, prepare deviation report including justification of acceptance and its impact on performance.



Prepare a PQ report.



Submit PQ document to QA for approval and review.38

42

A REVIEW ON PHARMACEUTICAL VALIDATION

3. Areas of Validation Manufacturing pharmaceutical products is a highly controlled process, whether the end product is aseptic, terminally sterilized, lyophilized, or even an originating bulk ingredient. Therefore, the environments in which the activities of manufacture are performed must be controlled and through monitoring proven to be in control. In a pharmaceutical industry, several of its areas are regularly validated as per the requirements. Such validation entails detailed measuring of various physical parameters throughout the sterilization process and assessing and comparing these results to relevant international standards. The list of areas of validation is as follows:

1. Process validation 2. Analytical method validation 3. Facilities validation 4. Computer system validation 5. Environmental validation 6. Equipment validation a. HVAC validation b. HPLC validation 7. Raw material or vendor validation 8. Cleaning validation 9. Cold chain validation 10. Personal validation

43

A REVIEW ON PHARMACEUTICAL VALIDATION

3.1 Process Validation US FDA defines process validation as ―establishing documented evidence which provides a high degree of assurance that a specified process will consistently produce a product meeting its predetermined specifications and quality characteristics.‖ In recent days, FDA modified the definition of process validation as ―the collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product.‖ ICH defined process validation as ―the means of ensuring and providing documentary evidence that processes within their specified design parameters that are capable of repeatedly and reliably producing a finished product of the required quality.‖ WHO defined it as ―the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to expected results.‖39 The term process validation should be reserved for the final stage(s) of the product/process development sequence. Product design

Product characterization Product selection (―go‖ formula) Process design Product optimization Process characterization Process optimization Process demonstration Process validation program Product/process certification Process validation is assigned at the end of the sequence so that the specific exercise of process validation should never be designed to fail. If the process validation assignment is failed, it is 44

A REVIEW ON PHARMACEUTICAL VALIDATION considered that process‘s capability (what the process can and cannot do under a given set of operational) is monitored incompletely.

3.1.1 Pilot Scale-Up and Process Validation Before preparation of the first pilot-production batch following development activities are performed. 1. Formulation design, selection, and optimization. 2. Preparation of the first pilot-laboratory batch. 3. Conduct initial accelerated stability testing. 4. If the formulation is deemed stable, preparation of additional pilot laboratory batches of the drug product for expanded nonclinical and/or clinical use. A. Laboratory Batch It is the selection of a suitable preliminary formula for more critical study. It is a testing based on certain agreed-upon initial design criteria, requirements, and/or specifications. The work is performed in the development laboratory. Batch Size:

— usually 3–10 kg of a solid or semisolid — 3–10 liters of a liquid — 3000 to 10,000 units of a tablet or capsule. B. Laboratory Pilot Batch After passing the accelerated stability testing (e.g., 1 month at 45°C or 3 months at 40°C or 40°C/80% RH), the next step in the scale-up process is the preparation of the (10 ×) laboratory pilot batch. Batch Size:

— 30–100 kg of a solid or semisolid — 30–100 liters of a liquid — 30,000 to 100,000 units of a tablet or capsule. The number and actual size of the laboratory pilot batches may vary in response to one or more of the following factors: 1. Equipment availability 2. Active pharmaceutical ingredient (API) 45

A REVIEW ON PHARMACEUTICAL VALIDATION 3. Cost of raw materials 4. Inventory requirements for clinical and nonclinical studies. C. Pilot Production This phase may be carried out either as a shared responsibility between the development laboratories and its appropriate manufacturing counterpart or as a process demonstration by a separate, designated pilot-plant or process-development function. Pilot Plant

Development Laboratory

Production

Pilot Batch Request

Development Laboratory

Production Pilot Batch Completion Report

Figure: Main piloting options (Top). Separate pilot plant functions—engineering concept. (Bottom) Joint pilot operation. It targeted to scale the product and process by another order of magnitude (e.g. 100 ×) to change batch size significantly for required additional validation studies. The number of batches can depend on several factors including but not limited to: 1. The complexity of the process being validated; 2. The level of process variability; and 3. The amount of experimental data and/or process knowledge available on the specific process.

3.1.2 Priority Order in Process Validation The following order of importance or priority with respect to validation is suggested: A. Sterile Products and Their Processes: 1. Large-volume parenterals (LVPs) 2. Small-volume parenterals (SVPs) 3. Ophthalmics, other sterile products, and medical devices B. Non-sterile Products and Their Processes: 1. Low-dose/high-potency tablets and capsules/transdermal delivery systems (TDDs) 46

A REVIEW ON PHARMACEUTICAL VALIDATION 2. Drugs with stability problems 3. Other tablets and capsules 4. Oral liquids, topicals, and diagnostic aids.

3.1.3 Stages of Process Validation Process validation involves a series of activities taking place over the lifecycle of the product and process. Process validation activities describes in three stages. Stage 1 ― Process Design It is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. At this stage, a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes is designed. A. Building and Capturing Process Knowledge and Understanding 1. Design of Experiment (DOE) studies o For justification of establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. 2. Revealing relationships of multivariate interactions, between the variable inputs (e.g., component characteristics or process parameters) and the resulting outputs (e.g., inprocess material, intermediates, or the final product). 3. Risk analysis tools to screen potential variables for DOE studies. o To minimize the total number of experiments conducted while maximizing knowledge gained. 4. Experiments or demonstrations at laboratory or pilot scale. o To evaluate certain conditions and prediction of performance of the commercial process. o To provide information that can be used to model or simulate the commercial process. 5. Computer-based or virtual simulations of certain unit operations or dynamics. o Provide process understanding. o Help avoid problems at commercial scale.

47

A REVIEW ON PHARMACEUTICAL VALIDATION 6. Studding documentation procedure of activities and studies resulting in process understanding o Reflect the basis for decisions made about the process. o E.g. variables studied for a unit operation and the rationale for those variables is useful during the process qualification and continued process verification stages. B. Establishing a Strategy for Process Control Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. To reduce and adjust input variation during manufacturing is the objective of process control. Recommendations: 1. Control both examination of material quality and equipment monitoring. 2. Control the process through operational limits and in-process. –

When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination).

–

When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

3. Timely analysis and control loops to adjust the processing conditions so that the output remains constant. 4. Controls operational limits. The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation. Stage 2 ― Process Qualification During this stage, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. For commercial distribution, successful completion of Stage 2 is necessary.40 Products manufactured during this stage, if acceptable, can be released for distribution. This stage has 3 elements: A. Design of a Facility and Qualification of Utilities and Equipment Qualification of utilities and equipment generally includes the following activities: 1. Selecting utilities and equipment construction materials, operating principles. 48

A REVIEW ON PHARMACEUTICAL VALIDATION 2. Verifying that utility systems and equipment are built and installed in compliance with the design specifications. 

e.g. Built as designed with proper materials, capacity, and functions, and properly connected and calibrated.

3. Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. 

This should include challenging the equipment or system functions while under load comparable to that expected during



It should also include the performance of interventions, stoppage, and start-up as is expected during routine production.



Operating ranges should be shown capable of being held as long as would be necessary during routine production.

B. Process Performance Qualification (PPQ) It combines the actual facility, utilities and equipment (each now qualified). It also combines the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. Criteria: 1. PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance. 2. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch. 3. The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. C. PPQ Protocol It is a written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. Protocols discuss the following elements: 1. The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs. 2. The data to be collected, when and how it will be evaluated. 49

A REVIEW ON PHARMACEUTICAL VALIDATION 3. Tests to be performed (in-process, release, characterization) and acceptance criteria

for

each significant processing step. 4. The sampling plan, including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. 5. Criteria and process performance indicators that allow for a science- and risk-based decision. The criteria should include: 

A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability).



Provision for addressing deviations from expected conditions and handling of nonconforming data.

6. Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources. 7. Status of the validation of analytical methods used in measuring the process, in-process materials, and the product. 8. Review and approval of the protocol by appropriate departments and the quality unit.

D. PPQ Protocol Execution and Report After review and approved by all appropriate departments, including the quality unit execution of the PPQ, protocol should begin. If any deviations, it must be justified and approved by all appropriate departments and the quality unit before implementation.  Criteria followed during PPQ Execution 1. The commercial manufacturing process and routine procedures must be followed during PPQ protocol execution. 2. The PPQ lots should be manufactured under normal conditions by the personnel routinely expected to perform each step of each unit operation in the process. — Normal operating conditions include 

the utility systems (e.g., air handling and water purification)



material



personnel



environment



manufacturing

50

A REVIEW ON PHARMACEUTICAL VALIDATION  Report A report should be prepared in a timely manner after the completion. This report should: 1. Discuss and cross-reference all aspects of the protocol. 2. Summarize data collected and analyze the data, as specified by the protocol. 3. Evaluate any unexpected observations and additional data not specified in the protocol. 4. Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls. Stage 3 ― Continued Process Verification At this stage, it is assured that the process remains in a state of control (the validated state) during commercial manufacture and the unplanned departures from the process is designed. In this phase, undesired process variability is detected and evaluated which identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems to control process.41  Recommendations: 1. Procedures should describe how trending and calculations are to be performed and should guard against overreaction, and failure to detect unintended process variability. 2. Production data should be collected to evaluate process stability and capability. The quality unit should review this information.42

3. The data should be statistically trended and reviewed by trained personnel. — A statistician develop : 

The data collection plan and statistical methods



Procedures used in measuring and evaluating process stability and process capability.43

4. The quality units meet periodically with production staff to evaluate data, discuss possible trends or undesirable process variation, and coordinate any correction or follow-up actions by production.44

5. The equipment and facility qualification data should be assessed periodically to determine whether re-qualification should be performed. 6. Once established, qualification status must be maintained through routine monitoring, maintenance, and calibration procedures and schedules. 51

A REVIEW ON PHARMACEUTICAL VALIDATION 3.1.4 Types of process validation 3.1.4.1 Prospective process validation It is defined as the established documented evidence that a system does what it purports to do based on a preplanned protocol. Its objective is to prove or demonstrate that the process will work in accordance with validation protocol prepared for the pilot production trials. Prospective validation requires a planned program and organization to carry it to successful completion. The organization must have clearly defined areas of responsibility and authority for each of the groups involved in the program. In this type, structure must be tailored to meet the requirements and an effective project management structure will have to be established.  Master Documentation: An effective prospective validation program must be supported by documentation extending from product initiation to full-scale production. The master documentation file should contain all information that was generated during the entire product development sequence to a validation process.  Product Development It begins when an active chemical entity shows the necessary attributes for a commercial product. This activities form the foundation upon which the subsequent validation data are built. This can sub-divide into formulation and process development, along with scale-up development. A. Formulation Development It provides the basic information on the active chemical, the formula, and the impact of raw materials or excipients on the product. 1. Preformulation profile or characterization of the components of the formula. 2. Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies, and the effect of formulation on in vitro dissolution. 3. Effect of formulation variables on the bioavailability of the product. 4. Specific test methods. 5. Key product attributes and/or specifications. 6. Optimum formulation. 7. Development of cleaning procedures and test methods. 52

A REVIEW ON PHARMACEUTICAL VALIDATION B. Process Development They may occur after the formulation has been developed simultaneously. Major activities occur either in the pilot plant or in the proposed manufacturing plant. It should have following objectives: 1. Develop a suitable process to produce a product that meets all product specifications, economic constraints and cGMPs. 2. Identify the key process parameters that affect the product attributes. 3. Identify in-process specifications and test methods. 4. Identify generic and/or specific equipment that may be required. Cleaning procedures should at least be in the final stages of development. Process development can be divided into several stages. a. Design: It includes following 1. Prepare flow diagram. 2. Prepare influence matrix. 3. Establish experimental procedure. 4. Establish design criteria. 5. Prepare study plan and protocols. b. Challenging of critical process parameters: 1. Identify critical variables for unit and overall operation. 2. Establish maximum tolerance for process variables. These studies determine: 

The feasibility of the designed process.



The criticality of the parameters.

c. Process characterization: 1. Modify study plan and protocols. 2. Establish nominal values for critical values. 3. Establish tolerances for critical variables. The objectives of these studies are 1. Confirm critical process parameters and determine their effects on product quality attributes. 2. Establish process conditions for each unit operation. 3. Determine in-process operating limits to guarantee acceptable finished product and yield. 53

A REVIEW ON PHARMACEUTICAL VALIDATION 4. Confirm the validity of the test methods. d. Process Verification: 1. Modify study plan and protocols 2. Determine product variability under constant processing conditions 3. Prepare process transfer documents 4. Finalize product specification e. Development Documentation: The developmental document to support the validation of the process may contain the following: 

Process challenging and characterization reports



Development batch record



Raw material test methods and specifications



Equipment list and qualification and calibration status



Process flow diagram



Process variable tolerances



Operating instructions for equipment (where necessary)



In-process quality control program



Critical unit operation



Final product specifications



Special production facility requirements



Cleaning Procedure for equipment and facilities



Test methods



Stability profile of the product



Produced during process development



Primary packaging specification

 Development of Manufacturing Capability There must be a suitable production facility for every manufacturing process that is developed. This facility includes buildings, equipment, staff, and supporting functions.  Full-Scale Product/Process Development The development of the final full-scale production process proceeds through the following steps: a. Process scale-up studies

54

A REVIEW ON PHARMACEUTICAL VALIDATION Careful planning and implementation requires during transition of successful pilot-scale process or research scale to a full-scale process. b. Qualification Trials After completing scale-up studies it may be necessary to manufacture one or more batches at full scale to confirm that the entire manufacturing process can be carried out smoothly. This may occur prior to or after the regulatory submission, depending on the strategy used in filing. c. Process Validation Runs After completing the qualification trials, the protocol for the full-scale process validation runs can be written. Current industry standard for the validation batches is manufactured for both process parameters and specifications. FDA has determined that the minimum number of validation batches should be three.

Master Product Document An extensive quantity of documents is generated at each stage of the development and validation of the final production process. Some of these documents will be directly related to the manufacture of the final products. The documents that are required for manufacturing the product then become the master product document. Items that will normally be included in the master product document are1. Batch manufacturing record 2. Master formulation 3. Process flow diagram 4. Master manufacturing instructions 5. Master packaging instructions 6. Specifications 7. Sampling (location and frequency) 8. Test methods 9. Process validation data  Defining Experimental Programs Its purpose is to examine experiments or combinations of related experiments for developing justification of formulation. Topics to be discussed include 1. Defining program scope 55

A REVIEW ON PHARMACEUTICAL VALIDATION — The definition of specific experimental objectives can be a continuing activity throughout product development. — The effect and impact of time, resources, and budget should be incorporated into the experimental program to avoid critical program objectives. 2. Process summary — Flow Diagram 

Provide a focal point of early program planning activities.



Provides a convenient basis on which list of variables and responses is developed.

— Variables and Responses 

Once properly identified, the list of variables and responses for the process is not likely to change appreciably.

— Cause-and-Effect Diagram 

Principle factors of each process step that can cause or influence the effect are drawn as sub branches of each branch, until a complete cause-and-effect diagram is developed.

Figure 3: Cause-and-effect diagram (granulated product). 56

A REVIEW ON PHARMACEUTICAL VALIDATION 3. Experimental design and analysis Many different experimental designs and analysis methods can be used in development activities. In general, designs that are usable offer different levels of efficiency, complexity, and effectiveness in achieving experimental objectives. 4. Experiment documentation 5. Program organization

3.1.4.2 Concurrent Validation It is a process where current production batches are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch.43 Concurrent Validation may be the practical approach under certain circumstances. Examples of these may be when: 1. A previous validated process is being transferred to a third party contract manufacturer or to another site. 2. The product is a different strength of a previously validated product with the same ratio of active/inactive ingredients. 3. The numbers of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control. 4. The numbers of batches produced are limited. 5. Process with low production volume per batch and market demand. 6. Process of manufacturing urgently needed drug due to shortage or absence of supply. In all above cases, concurrent validation is valid, provided following conditions are appropriately. 1. Pre-approved protocol for concurrent validation with rational 2. A deviation shall be raised with justification and shall be approved by plant head /head process owner/Head-QMS. 3. Product behavior and history shall be reviewed based on developmental/scale up /test batches. 4. A detailed procedure shall be planned for handling of the marketed product if any adverse reactions observed in concurrent validation process. 57

A REVIEW ON PHARMACEUTICAL VALIDATION 5. Concurrent validation batches shall be compiled in interim report and shall be approved all key disciplines.44

3.1.4.3 Retrospective Validation Conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which is now to be validated to confirm to the requirements of division 2, Part C of the Regulation to be Food and Drugs Act. Retrospective Validation is only acceptable for well-established detailed processes and will be inappropriate where there have recent changes in the formulation of the products, operating procedures, equipment and facility.45 Some of the essential elements for Retrospective Validation are: 1. Batches manufactured for a defined period (minimum of 10 last consecutive batches). 2. Number of lots released per year. 3. Batch size/strength/manufacturer/year/period. 4. Master manufacturing/packaging documents. 5. List of process deviations, corrective actions and changes to manufacturing documents. 6. Data for stability testing for several batches. 7. Trend analysis including those for quality related complaints.

3.1.4.4 Process Re-Validation Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricator, major equipment or premises. Failure to meet product and process specifications in batches would also require process re-validation.45 Re-Validation becomes necessary in certain situations. The following are examples of some of the planned or unplanned change that may require re-validation: 1. Changes in raw materials (physical properties such as density, viscosity, particle size

distribution, and moisture, etc., that may affect the process or product). 2. Changes in the source of active raw material manufacturer. 3. Changes in packaging material (primary container/closure system). 58

A REVIEW ON PHARMACEUTICAL VALIDATION 4. Changes in the process (e.g., mixing time, drying temperatures and batch size). 5. Changes in the equipment (e.g. addition of automatic detection system). 6. Changes of equipment which involve the replacement of equipment on a “like for like basis

would not normally require a revalidation except that this new equipment — Must be qualified. — Changes in the plant/facility.

— Variations revealed by trend analysis (e.g. process drifts).46 3.1.5 Process Validation Decision45 a) Process Validation Decision Tree for change in process controls of manufacturing process of drug products:

59

A REVIEW ON PHARMACEUTICAL VALIDATION b) Process Validation Decision Tree for Change in Manufacturing Site of Drug Product:

c) Process Validation Decision Tree for Change in Batch size of drug Product:

d) Process Validation Decision Tree for Change in Equipment:

60

A REVIEW ON PHARMACEUTICAL VALIDATION e) Process Validation Decision Tree for Change in Source of Active Pharmaceutical Ingredients (API).

f) Process Validation Decision Tree for Change in Source of Excipient

61

A REVIEW ON PHARMACEUTICAL VALIDATION 3.1.6 Sterilization Validation Sterilization processes require periodic validation to demonstrate that they are working correctly and functioning within established norms. Such validation entails detailed measuring of various physical parameters throughout the sterilization process and assessing and comparing these results to relevant international standards. The production of sterile preparations should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate standard of cleanliness and supplied with air that has passed through filters of the required efficiency. Manufacturing operations are divided here into two categories a. Those where the product is terminally sterilized, b. Those which are conducted aseptically at some or all stages.

3.1.6.1 Requirement of validation Sterile Preparations refers to the intent of preventing harm and fatality to patients that could arise from microbial contamination or excessive bacterial end toxins. But during manufacturing and compounding, there is risk of microbial contamination despite of all the precautions taken in the pharmaceuticals. Some sources of microbial contamination in aseptic processing area are as follows46: 

Personnel borne contaminants



Human error



Non-routine operations during aseptic process



Assembly of sterile equipment prior to use



Mechanical failure



Inadequate or improper sanitation



Transfer of materials within APA



Routine operations during aseptic process



Airborne contaminants



Surface contaminants



Failure of sterilizing filter



Failure of HEPA filter 62

A REVIEW ON PHARMACEUTICAL VALIDATION 

Inadequate or improper sterilization.

3.1.6.2 Principles of validation of sterilization processes 1. The process equipment has the capability of operating under a controllable set of conditions. These conditions depend on the sterilizing agent used. 2. The control equipment can operate within the limits needed to ensure reproducibility and accuracy of the parameters of the sterilization equipment. 3. Replicate sterilization cycles are used to test the operational ranges of the equipment and the impact on the probability of survival of micro-organisms. 4. Validated process will have to be monitored during routine operation and also needs to be requalified at periodical intervals. 5. Sterilization cycles are developed then validated with the help of biological indicators (BIs) specific for the sterilizing agent that is used. 6. Document and archive data from all the steps above in a retrievable fashion. 3.1.6.3 Clean room Certification47: The certification state of the clean room must be determined in advance of testing; three states exist within the manufacturing facility, such as: 

As Built: A completed room with all services connected and functional, but without production equipment or personnel within the facility.



At Rest: A room where all the services are connected, all the equipment is installed and operating to an agreed manner, but no personnel are present.



Operational: All equipments are installed and are functioning to an agreed format, and a specified number of personnel are present working to an agreed procedure.

3.1.6.4 Manufacture of sterile preparations48 For the manufacture of sterile pharmaceutical preparations, four grades are distinguished here, as follows: • Grade A: The local zone for high-risk operations, e.g. filling and making aseptic connections. Normally such conditions are provided by a laminar-airflow workstation. Laminar-airflow

63

A REVIEW ON PHARMACEUTICAL VALIDATION systems should provide a homogeneous air speed of approximately 0.45m/s ± 20% (guidance value) at the working position. • Grade B: In aseptic preparation and filling, the background environment for the grade A zone. • Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products To obtain air of the required characteristics, methods specified by national authorities should be used. In order to reach the B, C and D grades, the number of air changes should be appropriate for the size of the room and the equipment and personnel present in it. At least 20 air changes per hour are usually required for a room with a good airflow pattern and appropriate high-efficiency particulate air (HEPA) filters.

3.1.6.5 How to validate The sterility test applied to the finished product should be regarded as the last step of control measures by which sterility is assured. The test should be validated for all the products. The sterility of the finished product is assured by the validation of the sterilization cycle in the case of terminally sterilized products, and by ―media simulation‖ or ―media fill‖ runs for aseptically processed products. Batch-processing records and, in the case of aseptic processing, environmental quality records, should be examined in conjunction with the results of the sterility tests. For injectable products the water for injection and the intermediate, if appropriate, and finished products should be monitored for endotoxins, using an established pharmacopoeial method that has been validated for each type of product. For large-volume infusion solutions, such monitoring of water or intermediates should always be done, in addition to any tests required by an approved monograph for the finished product. When a sample fails a test, the cause of the failure should be investigated and necessary action should be taken.

3.1.6.6 Process Simulation Test It uses a nutrient medium (media fill). Selection of the nutrient medium is made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilization of the nutrient medium. It is performed by running three consecutive satisfactory simulation tests. 64

A REVIEW ON PHARMACEUTICAL VALIDATION These tests should be repeated at defined intervals and after any significant modification to the heating, ventilation and air-conditioning (HVAC) system, equipment or process. It should incorporate activities and interventions known to occur during normal production as well as the worst-case situation. The process simulation tests should be representative of each shift and shift changeover to address any time-related and operational features. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should be applied: 

When filling fewer than 5000 units, no contaminated units should be detected.



When filling 5000 – 10000 units, o One contaminated unit should result in an investigation, including consideration of a repeat media fill; o Two contaminated units are considered cause for revalidation following investigation;



When filling more than 10000 units: o One contaminated unit should result in an investigation; o Two contaminated units are considered cause for revalidation following investigation.

All sterilization process should be validated. Before choosing/adopting the sterilization process, its suitability for the product and its efficacy to achieve desired sterilized conditions should be demonstrated by physical measurements and by biological indicators, where appropriate. The validity should be verified at scheduled intervals, at least annually, and whenever significant modifications have been made. Records should be kept of all results.

65

A REVIEW ON PHARMACEUTICAL VALIDATION

3.2 Analytical method validation Analytical method validation is the process to confirm that the analytical procedure employed for a specific test is suitable for its intended use.49 It is the process of proving that an analytical method is acceptable for its intended purposes. METHOD VALIDATION = ERROR ASSESSMENT ISO defines method validation as ―confirmation by examination and provision of evidences that the particular requirements for a specified intended use are fulfilled. For pharmaceutical world, the meaning of analytical methods validation is the process to confirm that a method does what it purports to do, that is, to document through laboratory studies that the measurement procedure can reliably assess the identity, strength, and/or quality of a bulk drug substance, excipient or finished product. It should follow a life cycle approach (Figure below). Following this approach, validation activities should be performed and completed prior to release of Phase I clinical material and continually be updated, as needed, throughout product development, culminating in the validation for regulatory filing for licensing.

Figure 3: Schematic of test method life cycle 66

A REVIEW ON PHARMACEUTICAL VALIDATION 3.2.1 Why analytical methods need to be validated? Methods need to be validated or revalidated as follows: 1. Before their introduction into routine use. 2. Whenever the conditions change for which the method has been validated (e.g., instrument with different characteristics). 3. Whenever the method is changed, and the change is outside the original scope of the method. 4. When quality control indicates an established method is changing with time. 5. In order to demonstrate the equivalence between two methods (e.g., a new method and a standard).

3.2.2 Types of analytical procedures to be validated Discussion of the validation of analytical procedures is directed to the four most common types of analytical procedures: 1. Identification tests 

Intended to ensure the identity of an analyte in a sample.



Normally achieved by comparison of a property of the sample (e.g., spectrum, chromatographic behavior, chemical reactivity, etc.) to that of a reference standard

2. Quantitative tests for impurities content

3. Limit tests for the control of impurities — Either a quantitative test or a limit test for the impurity in a sample. — Quantitative test or a limit test are Intended to accurately reflect the purity characteristics of the sample. 4. Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product 3.2.3 Advantages of analytical method validation 1. It builds a degree of confidence, not only for the developer but also to the user. 2. It results inexpensive, eliminates frustrating repetitions and leads to better time management in the end. 3. Method validation absorbs the shock of changes in the conditions such as reagent supplier or grade, analytical setup. 67

A REVIEW ON PHARMACEUTICAL VALIDATION 3.2.3 Strategy for validation of methods The validity of a specific method should be demonstrated in laboratory experiments using samples or standards that are similar to the unknown samples analyzed in the routine. The preparation and execution should follow a validation protocol, preferably written in a step by step instruction format. Possible steps for a complete method validation are listed below: Develop a validation protocol or operating procedure for the validation

Define the application, purpose and scope of the method Define the performance parameters and acceptance criteria Define validation experiments Verify relevant performance characteristics of equipment Qualify materials, e.g. standards and reagents Perform pre‐validation experiments Adjust method parameters or/and acceptance criteria if necessary Perform full internal (and external) validation experiments Develop SOPs (standard operating procedures) for executing the method in the routine Define criteria for revalidation Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine Document validation experiments and results in the validation 3.2.4 Analytical procedure The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc. 68

A REVIEW ON PHARMACEUTICAL VALIDATION 3.2.4.1 Assay Characteristics/parameters to be validated The table below shows the validation parameters required for different types of methods per ICH Q2A and Q2B for commercial validation

3.2.5 Validation Parameters A. Specificity Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s). This definition has the following implications: Identification: to ensure the identity of an analyte. Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc. Assay (content or potency): To provide an exact result that allows an accurate statement on the content or potency of an analyte in a sample. B. Accuracy The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the 69

A REVIEW ON PHARMACEUTICAL VALIDATION value found.50 The accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value.51 Methods: 1. Analyzing a sample of known concentration of well characterized (e.g., reference standard) and comparing the measured value to the ‗true‘ value. 2. Spiked – placebo (product matrix) recovery method: A known amount of pure active constituent is added to formulation blank [sample that contains all other ingredients except the active(s)], the resulting mixture is assayed and the results obtained are compared with the expected result. 3. Standard addition method49: A sample is assayed A known amount of pure active constituent is added Sample is again assayed

The difference between the results of The two assays is compared with the expected answer Recommended Data: Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3 concentration levels covering the specified range (e.g., 3 concentrations/3 replicates each of the total analytical procedure).48 Calculation: Accuracy is calculated as the percentage of recovery by the assay of the known added amount of analyte in the sample, or as the difference between the mean and the accepted true value, together with confidence intervals. Assessment: It can be accomplished in a variety of ways such as – 1. Evaluating the recovery of the analyte (percent recovery) across the range of the assay. 2. Evaluating the linearity of the relationship between estimated and actual concentrations.

70

A REVIEW ON PHARMACEUTICAL VALIDATION The confidence interval for the slope be contained in an interval around 1.0, or alternatively, that the slope be close to 1.0.49 C. Precision Precision expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.48 It is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of a homogeneous sample.52 Precision should be investigated using homogeneous, authentic samples. If not possible to obtain a homogeneous sample, it may be investigated using artificially prepared samples or a sample solution. The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility. 1. Repeatability Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.48 It involves analysis of replicates by the analyst using the same equipment and method and conducting the precision study over short period of time. Repeatability should be assessed using a minimum of 9 determinations covering the specified range for the procedure (e.g., 3 concentrations/3 replicates each); or a minimum of 6 determinations at 100% of the test concentration. The RSD(relative standard deviation) values are important for showing degree of variation. 

RSD below 1% for built drugs



RSD below 2% for assays in finished product.

2. Intermediate precision Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc. 

Effects of random events on the precision of the analytical procedure should be studied



Typical variations to be studied include days, analysts, equipment, etc.



The use of an experimental design (matrix) is encouraged. 71

A REVIEW ON PHARMACEUTICAL VALIDATION 3. Reproducibility Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).48 

It involves precision study at different occasions, different laboratories and different batch of reagent, different analysts and different equipment.49



Reproducibility is assessed by means of an inter-laboratory trial (by different analysts, by the use of different equipment, or by carrying out the analysis at different times).48

D. Limit of Detection The Limit of Detection is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. It is a limit that specifies whether or not an analyte is above or below certain value.48 The Limit of Detection is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample. There are two methods of determining the limit of detection. They are as follow: 1. Non instrumental procedures The detection limit is generally determined by a. The analysis of samples with known concentrations of analyte b. Establishing the minimum level at which the analyte can be reliably detected. 2. Instrumental procedures In this method, measured signals from samples with known low concentrations of analyte are compared with those of blank samples. The minimum concentration at which the analyte can reliably be detected is established. Typically acceptable signal-to-noise ratios are 2:1 or 3:1. The signal‐to noise ratio is determined by dividing the base peak by the standard deviation of all data points below a set threshold. Calculation: Limit of detection is calculated by taking the concentration of the peak of interest divided by three times the signal‐to‐noise ratio.49 E. Limit of Quantitation. The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products. 72

A REVIEW ON PHARMACEUTICAL VALIDATION It is determined by analyzing samples containing known quantities of the analyte and determining the lowest level at which acceptable degrees of accuracy and precision are attainable. In the case where final assessment is based on an instrumental reading, it is determined from the magnitude of background response by analyzing a number of blank samples and calculating the standard deviation of this response. The standard deviation multiplied by a factor (usually 10) provides an estimate of the limit of quantitation. In many cases, the limit of quantitation is approximately twice the limit of detection. F. Linearity The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.48 Thus ―linearity‖ refers to the linearity of the relationship of concentration and assay measurement. Linearity should be established across the range of the analytical procedure. 1. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. 2. If there appears to be a linear relationship, test results should be established by appropriate statistical methods (e.g., by calculation of a regression line by the method of least squares). 3. Data obtained from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity.49 For the establishment of linearity, a minimum of 5 concentrations is recommended.48 The working sample concentration and samples tested for accuracy should be in the linear range. Data is processed by linear least square regression declaring the regression co‐efficient and b of the linear equation, y = ax + b together with the correlation coefficient of determination r. For the method to be linear the r value should be close to ±1.49 G. Range The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity. The following minimum specified ranges should be considered:

73

A REVIEW ON PHARMACEUTICAL VALIDATION 1. For the assay of a drug substance or a finished (drug) product: normally from 80 to 120 percent of the test concentration; 2. For content uniformity: covering a minimum of 70 to 130 percent of the test concentration, unless a wider more appropriate range, based on the nature of the dosage form (e.g., metered dose inhalers), is justified. 3. For dissolution testing: +/-20 % over the specified range. e.g., if the specifications for a controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours, the validated range would be 0-110% of the label claim. 4. For the determination of an impurity: Impurity must be within 1 – 120% of the specification. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the detection/quantitation limit should be commensurate with the level at which the impurities must be controlled; 5. If assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities1 to 120% of the assay specification. H. Robustness It is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.48 The robustness of a method is evaluated by varying method parameters such as percent organic solvent, pH, ionic strength, temperature and determine the effect (if any) on the results of the method.53 The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. Examples of typical variations are: 

Stability of analytical solutions;



Extraction time.

In the case of liquid chromatography, examples of typical variations are: 

influence of variations of pH in a mobile phase;



influence of variations in mobile phase composition;



different columns (different lots and/or suppliers);



temperature; 74

A REVIEW ON PHARMACEUTICAL VALIDATION 

flow rate.

In the case of gas-chromatography, examples of typical variations are: 

different columns (different lots and/or suppliers);



temperature;



flow rate.48

I. Ruggedness. The ruggedness of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of normal test conditions such as different laboratories, different analysts, using operational and environmental conditions that may differ but are still within the specified parameters of the assay. 

It is normally suggested when the method is to be used in more than one laboratory.



Normally expressed as the lack of the influence on the test results of operational and environmental variables of the analytical method.

For the determination of ruggedness, the degree of reproducibility of test result is determined as function of the assay variable. This reproducibility may be compared to the precision of the assay under normal condition to obtain a measure of the ruggedness of then analytical method.51 J. Stability and system suitability tests. Stability of the sample, standard and reagents is required for a reasonable time to generate reproducible and reliable results. For example, 24 h stability is desired for solutions and reagents that need to be prepared for each analysis. System suitability test provide the added assurance that on a specific occasion the method is giving, accurate and precise results. System suitability test are run every time a method is used either before or during analysis. The results of each system suitability test are compared with defined acceptance criteria and if they pass, the method is deemed satisfactory on that occasion. The nature of the test and the acceptance criteria will be based upon data generated during method development optimization and validation experiments. Document of system suitability can be accomplished by using software specifically designed for the task to provide a review of method development and to summarize the data regarding reproducibility.54

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A REVIEW ON PHARMACEUTICAL VALIDATION 3.2.6 Data Elements Required for Validation There are various analytical methods used for the examination of pharmaceutical materials. Here only the most common categories of tests for which validation data should be required is described. These categories are as follows: Category I — Analytical procedures for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products. Category II — Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These procedures include quantitative assays and limit tests. Category III — Analytical procedures for determination of performance characteristics. (e.g. Dissolution, drug release). Category IV — Identification tests. For each category, different analytical information is needed. Listed in table below are data elements that are normally required for each of these categories. Analytical

Assay

Assay

Assay

Performance

category I

category II

category III

Characteristics

Quantitative Limit tests

Tests

Assay

category IV

Accuracy

Yes

Yes

*

*

No

Precision

Yes

Yes

No

Yes

No

Specificity

Yes

Yes

Yes

*

Yes

Detection Limit

No

No

Yes

*

No

Quantitation

No

Yes

No

*

No

Linearity

Yes

Yes

No

*

No

Range

Yes

Yes

*

*

No

Limit

Where, * indicates that may be required depending on the nature of the specific test. Table 4: Characteristics required for assay validation as per USP

76

A REVIEW ON PHARMACEUTICAL VALIDATION

3.3 Facilities Validation The design, construction, and commissioning of a new facility for the pharmaceutical industry is a complex process that involves the interaction of a wide variety of engineering, process and QA, and control disciplines and may proceed through a series of different phases from a conceptual, feasibility study, through to the final detailed design, construction, commissioning, and final site validation activities. The consequence of this for the facility designer is that he or she must use design and engineering methods that will comply with and demonstrate that the facility, when complete, does meet the requirements of cGMP.55 The key basis to successfully qualify a facility is to plan the qualification from the earliest stage of the facility design by the development of a clear validation strategy that will develop into a plan for validation throughout the project. 3.3.1 The Engineering Design Process for a Facility The engineering design process typically follows a series of phases: 

Conceptual design



Design development, front-end design or basic/preliminary engineering



Detailed engineering



Procurement



Construction



Pre commissioning



Commissioning

Each of these phases has its own engineering objectives and consequently, the qualification requirements have both a different scope and extent at each phase. The concepts for qualification will be described for each phase.

3.3.2 Conceptual Design: Production of clinical trial material will have moved from laboratory facilities to pilot-scale operations. Experience gained at this pilot-scale production will normally give sufficient information to enable a process definition to be prepared. The marketing organization will also have some early projections for demand levels and the type of formulations that will be required. These key elements will give a basis for a conceptual design study. 77

A REVIEW ON PHARMACEUTICAL VALIDATION The collection of process data for subsequent full-scale PV will also already have begun. Clearly, the current regulatory bodies emphasis on proof of drug equivalence, i.e., final production batches must be equivalent in biological and chemical activity to those used in the clinical trial and any subsequent submissions (typically for the NDA) will already have some significant effect on the manufacturing route, engineering design, and equipment selection. The conceptual study must consider all these aspects and incorporate their requirements into this early design. Consequently a plan is required to ensure that GMP, qualification, and process requirements are incorporated.

3.3.3 Purposes: The main purposes of a conceptual study are as follows: 1. An agreed basis for the design philosophy to be able to proceed to the next phase of development. 2. To provide an initial capital cost estimate, usually for a preliminary budget sanction by senior management. 3. The typical deliverables of this phase are as follows: 

Statement of basis of design



GMP statement



Process block flow diagrams or schematics



Major equipment item list



Conceptual layout and accommodation schedule



Building and HVAC philosophy



Outline of utility systems



Outline of control philosophy



Safety considerations



Budget estimate

Usually, the conceptual study is run as a mixed disciplinary team bringing together research and development, production, and engineering disciplines led by a study manager. Although QA does not have a major role to play at this stage, it is important that the team has access to appropriate personnel.

78

A REVIEW ON PHARMACEUTICAL VALIDATION 3.3.4 Qualification Activities At this stage, the qualification of the facility is in its earliest phase and the emphasis must be on the qualification of the design. This can be completed by reviews of the proposed design against defined user requirements criteria. The preliminary nature of the study limits the depth of review. It should address critical issues against the user specification and the GMP requirements.

3.3.5 Qualification Cost Clearly if the conceptual phase is to provide a cost estimate for the project, then the qualification must be similarly estimated at this stage. Some form of qualification statement and policy is required to at least determine its future scope. Some may prefer to develop a very preliminary facility and equipment. The decision of which route to take may be determined by the extent of the study and company policy. Without significant details of the facility and its contents, specific costs for the key qualification tasks cannot be easily determined unless access to similar projects‘ costs is available. At this stage, it is probably more normal to make an allowance based on in-house or the design engineers‘ experience. It is important to have an estimate that reflects that of the study.

3.3.6 Design Development: Usually, by this phase of the project, the pharmaceutical company believes that it is highly probable that the project will precede subject perhaps to certain restrictions, usually based on schedule and total final cost.39 The answers of the following questions have significant bearing on the route adopted towards design development: 

Should this phase be done in house?



Involve an external design construction consultancy?



An Engineering Management Contractor?



Can the designer meet and demonstrate that the design complies with GMP?



Are you going to use a single engineering organization to manage the project through design, procurement, construction, commissioning, and qualification?



Are the systems in place to aid qualification?

79

A REVIEW ON PHARMACEUTICAL VALIDATION 3.3.6.1 Purposes The main objectives of this design development phase are as follows: 1. To establish a basis for detailed design. 2. To progress the design to establish the technical, capability, and safety aspects of the project. 3. To provide the necessary design data to evaluate subsequently and comply with the regulatory, environmental, and planning requirements of a project with the relevant authorities. 4. To provide an improved cost estimate and so enable sanction of the project. 5. Typical design development deliverables are as follows: 

Process flow diagrams



Process and equipment specifications



Utility specifications



Control and automation user requirements specification



Preliminary process PID



Floor plans and equipment layouts



Facility and equipment qualification plan



List of systems



Building evaluation



Building finishes



HVAC schematics and routings



Safety and GMP reviews



Environmental considerations



Project schedule



Estimate

3.3.7 Facility Qualification Plan To be able to execute facility validation, a plan is essential. For a single system, this is achieved through a protocol, which in simple terms is a plan, followed by its execution. For a whole facility and its operation, we require a plan that encompasses all aspects of validation and qualification and this is usually termed a Validation Master Plan. It would cover facility and equipment, automation, cleaning, process and Laboratory and analytical systems. These would

80

A REVIEW ON PHARMACEUTICAL VALIDATION often have their own sub plan and in the case of facility we have termed this the facility and equipment qualification (FEQ) plan.56 The typical contents of an FEQ are as follows: 

Introduction



Methodology



Qualification



DQ



IQ



OQ



PQ



Personnel and responsibilities



Schedule



Preventative maintenance



Change control



Procedures



Documentation



Appendices

The plan needs to be developed and to focus on those standards that must be met including regulatory requirements. The standards will normally comprise the following three elements: 

Regulatory and guidance documents



National standards (or equivalent)



Company standards

3.3.8 Qualification57 The primary objective of qualification is a critical review of the system, equipment, or facility against the design documents (especially specifications and P&IDs drawings) to confirm that the user requirements have been satisfied. One important issue is how to select the acceptance criteria for the various tests that are performed. For example, a shelf dryer is being used for drying of tablet granulation. The URS states the dryer to be capable of ±5°C, so vendor provides

81

A REVIEW ON PHARMACEUTICAL VALIDATION a dryer that has maximum variation of ±2°C.

It is recommended that putting the tighter

specification is better to be included. The reasons for doing so are as follows: 

If the system cannot meet this claim by the vendor perhaps there are other critical claims that the unit cannot meet.



A future product may be introduced that will require a tighter range and, if confirmed initially, there is no need to retest the dryer.



Having paid for a dryer that can maintain a tighter range, the owner should confirm that performance.

Table 5: Validation priorities for process and facility systems High: IQ/OQ/PQ (or PV)

Moderate: IQ/OQ

Low: Commission only

Breathing Air

Deionized water

Process

Water for injection/purified Vacuum

(if

used

in

drains

(except

the biotech)

water

process)

Non-process water

Clean steam

Controlled temperature rooms

Sanitary drains

Product contact gases

Process drains (biotech)

Electrical systems

Classified environments

Comfort HVAC

CIP system

Cooling water/jacket services

Solvent distribution systems

Instrument air

Process piping

Design Qualification It is performed to make a risk analysis and to check the design documents of a technical system to ensure that they fulfill the user requirements. It forms the basis for defining tests in the IQ, OQ and PQ phases. Installation Qualification The things that are considered in this phase are as follows: 

Provide as-built documentation (e.g. P&ID check).



Check training reports.



Check that documentation is complete.



Check calibration reports. 82

A REVIEW ON PHARMACEUTICAL VALIDATION 

Identify piping and instrumentation.

E.g. A sterile filling unit might include the following41 Premises Layout

Flow of personnel, product, raw materials, and such Finishes of walls, ceilings and floors

Utility services Drains

Water systems (e.g., cooling, hot and cold) Services gases (e.g., instrument air) Electrics HVAC class 100 systems Class 10,000 systems Class 100,000 systems

Process services

USP and WFI Process gases: nitrogen, propane, and others Clean steam

Equipment

Steam sterilizer Stopper washer—sterilizer Tray washer—autoclave Dry heat sterilizer Vessels Hot air tunnel sterilizer Ampoule or vial washing machine Filling and capping machines Lyophilizer Inspection line Labeler Packing (primary)

Operational Qualification: The typical tests in this phase include the following: 

Alarm tests



Behavior of the system after energy breakdown



Accuracy of filling lines 83

A REVIEW ON PHARMACEUTICAL VALIDATION 

Transportation speed in a sterilization tunnel



Temperature distribution in an autoclave



Performance of a washing machine



Accuracy of a weighing system.

The types of systems identified will be dependent on the nature of the facility, but a typical example list for a secondary sterile facility is given as follows:58 

Facility



HVAC class 100, 10,000, 100,000



WFI water



Process gases: air, nitrogen, CO2



Propane



SIP systems



CIP systems



Vial washer



Vial tunnel sterilizer



Vial filler and stopper machine



Lyophilizer



Vial capper



Vial inspection



Vial primary packing



Autoclave



Dry heat sterilizer



Stopper washer–autoclave



Solution preparation system

Performance Qualification 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.42 The technical systems that need to be performance-tested and qualified are as follows41: 84

A REVIEW ON PHARMACEUTICAL VALIDATION 

High purity water systems (monitoring of the quality parameters: pH, TOC, conductivity, CPU, temperature)



HVAC systems (temperature, pressure, humidity)



Complex connected systems (e.g. filling line, BPI production line; performance parameters).

85

A REVIEW ON PHARMACEUTICAL VALIDATION

3.4 Computer System Validation Computer system validation involves validation of Computer Related Systems (any place), Computer Systems & Operating

procedures, Design, Installation, Performance etc. This

method is to verify whether the computer systems are delivering their part. It includes hardware, software and the firmware. This method requires detailed documentation of the software or application used by the manufacturing process in the Pharmaceutical Company.59 A computer is a machine and like all other machines, it is normally used because it performs specific tasks with greater accuracy and more efficiency than people. Computers accomplish this by having the capacity to receive, retain, and give up large volumes of data and process in in a very short time. An understanding of computer operation, and the ability to use a computer, does not require a detailed knowledge of either electronics or the physical hardware construction. An overall view of the computer organization with emphasis on function is sufficient.60 3.4.1 History of computer system validation in brief61 •

1978 – Validation for GMP concept developed by FDA.

•

1979 – The USA issue Federal Regulations for GMP including validation of automation equipment.

•

1983 – FDA Blue Book for computer system validation.

•

1985 – US PMA published guideline for validating new and existing computer systems.

•

1987 – FDA technical report on developing computer systems.

•

1988 – FDA conference paper on inspecting computer systems.

•

1989 – EU Code for GMP including Annex 11 on computerized systems.

•

1991 – EU Directive for GMP based on EU Code for GMP.

•

1994 – GAMP first draft Distributed to U.K. for comments.

•

1995 – U.S. PDA publishes validation guideline for manufacturers.

•

1995 – The USA amends GMP regulations affecting automation.

•

1995 – U.K. FORUM revise draft guidelines to suppliers.

•

March of 1997, FDA issued final part 11 regulations

•

First Draft July, 2000 (GAMP Ameriacas)

•

Version 1 Quarter 2, 2001 (Co-Publication with PDA)

86

A REVIEW ON PHARMACEUTICAL VALIDATION •

GAMP4, December 2001, major revision and new content in line with regulatory and technological development.

•

February 4, 2003, FDA withdrew the draft guidance for industry, 21CFR Part 11.

3.4.2 Importance of CSV62 There are two key reasons why CSV is extremely important in the Life Science sector. They are as follows: 1. Systematic CSV helps prevent software problems from reaching production environments. A problem in a life science software application that affects the production environment can result in serious adverse consequences. Besides the obvious humanistic reasons that the life science sector strives to prevent such harm to people, the business consequences of a software failure affecting people adversely can include lawsuits, financial penalties and manufacturing facilities getting shut down. The ultimate result could be officers getting indicted, the company suffering economic instabilities, staff downsizing, and possibly eventual bankruptcy. 2. FDA regulations mandate the need to perform CSV and these regulations have the impact of law. Failing an FDA audit can result in FDA inspectional observations (―483s‖) and warning letters. Failure to take corrective action in a timely manner can result in shutting down manufacturing facilities, consent decrees, and stiff financial penalties. Again, the ultimate result could be loss of jobs, indictment of responsible parties (usually the officers of a company), and companies suffering economic instabilities resulting in downsizing and possibly eventual bankruptcy. Cutting corners on doing validation might save a little money in the short term but these saving will look minute and inconsequential in comparison to the costs and impacts of not doing validation correctly. 3.4.3 Typical Computer System Validation63 Document Name User

Function of Document in Validation

requirements Defines clearly and precisely what the user wants the system to do

Specifications (URS)

and states any constraints (e.g. regulatory) under which the system must operate. 87

A REVIEW ON PHARMACEUTICAL VALIDATION Validation Plan

Defines the objectives of the validation and the activities, procedures and responsibilities for accomplishing the objectives of the validation. The validation plan should also deal with the approach for maintaining the validation status. This will generally involve referencing

the

organization‘s

Quality

Management

System

documentation that deals with such issues as Configuration Management, Change Control, and System Retirement. Project Plan

Details the tasks and timeline for the project.

Documentation

Outlines the reasons for choosing the system including the results of

justifying Selection of auditing the supplier‘s quality management system. System

including

Supplier Audit Report Functional

Detailed specifications showing the functions that the system

Specifications

performs.

Design Specifications

Detailed specification showing how the system performs the functions documented in the Functional Specifications.

Supplier Test Plans Documentation of Supplier Testing and Results Task Reports

Documentation

of

Design/

Specification/

Testing

Reviews,

Walkthroughs, and Inspections. Traceability Matrix

Analysis document that shows mapping between URS, Functional Specs, Design Specs and test cases in IQ, OQ, PQ.

Risk Assessments

A Risk Assessment (sometimes called Failure Mode and Effects Analysis), is an analysis of failure scenarios associated with each of the functions and sub functions of a system. Each failure scenario is examined for potential business impact and likelihood of occurrence in order to determine the relative risks associated with each function and sub function of the system. Risk assessments may need to be performed at multiple strategic points in the SDLC.

Network Infrastructure

and Documentation that shows that the network and infrastructure hardware/software supporting the application System being validated 88

A REVIEW ON PHARMACEUTICAL VALIDATION Qualification

has been installed correctly and is functioning as intended.64

Installation

• Test cases for checking that system has been installed correctly in

Qualification

Scripts

User environment. • Results of executing scripts.

and Results

• Deviations from expected results (if any). • Test cases for checking that system has been installed correctly in

Operational Qualification

Scripts

User environment. • Results of executing scripts.

and Results

• Deviations from expected results (if any). SOPs,

Training Documented procedures for users, system administrators, and IT

Material, and Training related functions such as Backup & Restore and Archiving. Training Records

records must be kept to show the appropriate people were trained in the correct operation of the system. • Test cases for checking that System does what it is intended to do

Performance Qualification

Scripts

and Results

with trained people following SOPs in the production environment even under worst case conditions. • Results of executing scripts. • Deviations from expected results (if any).

Validation Report

This includes: • A review of all activities and documents against the Validation Plan. • Evidence that deviations (if any) have been addressed and the system is validated. • The plan for ongoing activities to maintain validation status.

3.4.4 Advantages of CSV65 To obtain the benefits of computer system validation it is important to implement a structured and professional validation process right from the start of the project. This will: 

Reduce cost and time you need in order to achieve compliance.



Ensure delivery on time, on budget with the necessary quality standards.



Satisfying the user immediately and in the long term. 89

A REVIEW ON PHARMACEUTICAL VALIDATION 

Ensure compliance with GxP and 21CFR Part 11 regulations (all automated systems that may have an impact on product quality, safety, identity or efficacy are subject to GxP rules).



Contribute to total product safety and traceability.



Improve change control and reduced support costs.

3.4.5 Software validation The Quality system regulation treats ―verification‖ and ―validation‖ as separate distinct terms whereas software engineers often use them interchangeably, or in some cases refer to software ―verification, validation, and testing (VV&T)‖ as if it is a single concept. Software verification provides objective evidence that the design outputs of a particular phase of the software development life cycle meet all the specified requirements for that phase. It looks for consistency, completeness, and correctness of the software and its supporting documents, as it is being developed, and provides support for a subsequent conclusion that software is validated. Software validation is a part of the design validation project for the project, but is not separately defined in the Quality System regulation. FDA considers it to be ―confirmation by examination and provision of objective evidence that software specifications conform to user needs and intended uses, and that the particular requirements implemented through software can be consistently fulfilled.‖ In practice, it may occur both during as well as end of the software development life cycle to ensure that all requirements have been fulfilled. It helps in developing a ―level of confidence‖ that the application meets all requirements and user expectations for the software automated functions.

3.4.6 Software Life Cycle Software validation takes place within the environment of an established software life cycle. Software life cycle contains software engineering tasks and documentation necessary to support the software validation effort. It also contains specific verification and validation tasks that are appropriate for the intended use of the software. The life cycle model selected should cover the software from its birth to its retirement. A series of activities and tasks are planned and executed at various stages of the software development

90

A REVIEW ON PHARMACEUTICAL VALIDATION lifecycle. During each of the activities; verification, testing and other tasks that support software validation occur. A typical software life cycle model includes the following66: 1. Quality Planning 2. System Requirements Definition 3. Detailed Software Requirements Specification 4. Software Design Specification 5. Construction or Coding 6. Testing 7. Installation 8. Operation and Support 9. Maintenance

3.4.6.1 Quality Planning The plan should include following – 

The specific tasks for each life cycle activity



Enumeration of important quality factors



Methods and procedures for each task



Task acceptance criteria



Criteria for defining and documenting outputs in terms that will allow evaluation of their conformance to input requirements



Inputs for each task



Outputs from each task



Roles, resources, and responsibilities for each task



Risks and assumptions



Documentation of user needs.

The typical tasks of quality planning includes following: 

Risk (Hazard) Management Plan



Configuration Management Plan



Software Quality Assurance Plan



Software Verification and Validation Plan 91

A REVIEW ON PHARMACEUTICAL VALIDATION 

Verification and Validation Tasks, and Acceptance Criteria



Schedule and Resource Allocation (for software verification and validation activities)



Reporting Requirements



Formal Design Review Requirements



-

Other Technical Review Requirements

-

Problem Reporting and Resolution Procedures

Other Support Activities

3.4.6.2 Requirements The typical software requirements specify the following: 

All software system inputs



All software system outputs



All functions that the software system will perform



All performance requirements that the software will meet



The definition of all external and user interfaces, as well as any internal software-to-system interfaces



How users will interact with the system



What constitutes an error and how errors should be handled



Required response times



The intended operating environment



All ranges, limits, defaults, and specific values that the software will accept



All safety related requirements, specifications, features, or functions that will be implemented in software.

The typical task includes: 

Preliminary Risk Analysis



Traceability Analysis



Software Requirements to System Requirements (and vice versa)



Software Requirements to Risk Analysis



Description of User Characteristics



Listing of Characteristics and Limitations of Primary and Secondary Memory 92

A REVIEW ON PHARMACEUTICAL VALIDATION 

Software Requirements Evaluation



Software User Interface Requirements Analysis



System Test Plan Generation



Acceptance Test Plan Generation



Ambiguity Review or Analysis

3.4.6.3 Design The software design specification should include following: 

Software requirements specification, including predetermined criteria for acceptance of the software



Software risk analysis



Development procedures and coding guidelines (or other programming procedures)



Systems documentation (e.g.,a narrative or a context diagram) that describes the systems context in which the program is intended to function, including the relationship of hardware, software, and the physical environment



Hardware to be used



Parameters to be measured or recorded



Logical structure(including control logic) and logical processing steps (e.g., algorithms)



Data structures and data flow diagrams



Definitions of variables (control and data)and description of where they are used



Error, alarm, and warning messages



Supporting software (e.g., operating systems, drivers, other application software)



Communication links (links among internal modules of the software, links with the supporting software, links with the hardware, and links with the user)



Security measures (both physical and logical security).

The typical tasks include: 

Updated Software Risk Analysis



Traceability Analysis - Design Specification to Software Requirements (and vice versa)



Software Design Evaluation



Design Communication Link Analysis 93

A REVIEW ON PHARMACEUTICAL VALIDATION 

Module Test Plan Generation



Integration Test Plan Generation



Test Design Generation (module, integration, system, and acceptance)

3.4.7 Construction or coding Software are constructed either by coding (i.e. programming) or by assembling together previously coded software components (e.g. from code libraries, off the-shelf software, etc.) for use in a new applications. Coding is the lowest level of the abstraction for the software development process where detailed design specification is implemented as source code. The tasks include: 

Traceability Analyses



Source Code to Design Specification (and vice versa)



Test Cases to Source Code and to Design Specification



Source Code and Source Code Documentation Evaluation



Source Code Interface Analysis



Test Procedure and Test Case Generation (module, integration, system, and acceptance)

3.4.8 Testing by the Software Developer It is important for early planning in order to be effective and efficient, although it‘s timeconsuming, difficult, and imperfect activity. Test plans and test cases should be created as early as possible in development process identifying schedules, environments, resources, methodologies, cases, documentation, and reporting criteria. The tasks include following 

Test Planning



Structural Test Case Identification



Functional Test Case Identification



Traceability Analysis - Testing



•

Unit (Module) Tests to Detailed Design

•

Integration Tests to High Level Design

•

System Tests to Software Requirements

Unit (Module) Test Execution 94

A REVIEW ON PHARMACEUTICAL VALIDATION 

Integration Test Execution



Functional Test Execution



System Test Execution



Acceptance Test Execution



Test Results Evaluation



Error Evaluation/Resolution



Final Test Report.

3.4.9 User Site Testing It is an essential part of software validation. The term ―user site testing ― encompasses terms such as beta test, site validation, user acceptance test, installation verification, and installation testing and any other testing that takes place outside of the developer‘s controlled environment. This should take place at a user‘s site with the actual hardware and software that will be part of the installed system configuration. It is accomplished either by actual or simulated use of software being tested within context in which it is intended to function. Typical tasks include following: 

Acceptance Test Execution



Test Results Evaluation



Error Evaluation/ Resolution



Final Test Report67

95

A REVIEW ON PHARMACEUTICAL VALIDATION

3.5 Equipment Validation Equipment validation comprehensively establishes in a documented way the instrument is working accurately. A validation process offers evidence that the components critically contributing to accurate functioning of the equipment consistently meet the predefined specifications and operational attributes.68 Equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out successfully. Equipment layout and design must aim to minimize risks of error to permit effective cleaning and maintenance and also to avoid cross-contamination, dust and dirt build-up any adverse effect on the quality of products.69 Equipment must be qualified to minimize risks of error and to minimize risks of contamination. Equipment validation through inspection, testing and documentation assures that: 

The correct equipment has been installed



The equipment has been properly installed



The equipment performs according to pre-established, written specifications.70

3.5.1 Reason of Equipment Validation 1. Validation of equipment is not just desirable, it is rather a necessity. All measuring instruments, whether they are used in factories, industries, need to be validation on a periodic basis to ensure they are offering accurate results. 2. Equipment validation is the hallmark of assurance that certifies the accurate functioning of an instrument under the prescribed range of operating environment and conditions, while steadfastly adhering to the correct operating specifications. 3. The non-compliance to GMP or other regulatory body‘s requirements may render the instrumentation of a company ineligible for industry use. This can spell significant losses for the company, further underlining the necessity of validation.55

3.5.2 Content of Equipment Validation a. Application of SOP‘s b. Utilization list c. Process description d. Test instrument utilized to conduct test 96

A REVIEW ON PHARMACEUTICAL VALIDATION e. Test instrument calibration f. Test function71

3.5.3 Balances and Measuring Equipment Appropriate range and precision available Mostly uses in production and quality control Calibrated –

scheduled basis

–

checks

–

records maintained

3.5.4 Production equipment Appropriate design –

easily and thoroughly cleaned on a scheduled basis

–

procedures and records

No hazard to the products –

contact parts of suitable non-reactive materials

–

non additive and

–

not absorptive

Defective equipment –

removed, or

–

labelled to prevent use

–

Closed equipment used when possible

–

Open equipment, or when equipment opened, precautions taken to prevent contamination

–

Non-dedicated equipment cleaned according to validated cleaning procedures between different products

–

Current drawings of critical equipment and support systems maintained

3.5.5 Control laboratory equipment Equipment and instruments − suitable for the tests to be performed 97

A REVIEW ON PHARMACEUTICAL VALIDATION Defective equipment − removed − labelled 3.5.6 Washing, cleaning and drying equipment Equipment used for washing and drying – not the source of contamination Equipment design should promote easy cleaning Cleaning on scheduled basis, procedures and records Washing and cleaning − manual − automated (Clean in place (CIP), Steam in place (SIP))72

3.5.7 Equipment Validation Process73:

Figure 6: Equipment Qualification Process 98

A REVIEW ON PHARMACEUTICAL VALIDATION DQ considerations included: 

Determine specified requirement of equipments



Defined capabilities e.g capacity, speed, range, temperature



Defined requirements e.g. size, power need, resistance to cleaning material



Additional Features e.g. ease of use, reputation, prior experience to same model, warranty, manufacturers support.74

IQ considerations included: • Equipment design features (i.e. material of construction clean ability, etc.) • Installation conditions (wiring, utility, functionality, etc.) • Calibration, preventative maintenance, cleaning schedules. • Safety features. • Supplier documentation, prints, drawings and manuals. • Software documented. • Spare parts list. • Environmental conditions (such as clean room requirements, temperature, and humidity). OQ considerations include: • Process control limits (time, temperature, pressure, line speed, setup conditions, etc.) • Software parameters. • Raw material specifications • Process operating procedures. • Material handling requirements. • Process change control. • Training. • Short term stability and capability of the process, (latitude studies or control charts). • Potential failure modes, action levels and worst-case conditions. • The use of statistically valid techniques such as screening experiments to optimize the process of equipment can be used during this phase. PQ considerations include: • Actual product and process parameters and procedures established in OQ. • Acceptability of the product. • Assurance of process capability as established in OQ. 99

A REVIEW ON PHARMACEUTICAL VALIDATION • Process repeatability, long term process stability by installed the equipment.75

3.5.8 HPLC method calibration HPLC is a form of liquid chromatography used to separate compounds that are dissolved in solution. HPLC instruments consist of –  a reservoir of mobile phase,  a pump,  an injector,  a separation column,  a detector.

Compounds are separated by injecting a sample mixture onto the column. The different component in the mixture passes through the column at different rates due to differences in their partition behavior between the mobile phase and the stationary phase. The mobile phase must be degassed to eliminate the formation of air bubbles.76 HPLC system calibration includes the pump, the detector, the auto sampler, and the column oven. Calibration procedures are often similar to those used in the initial operational qualification of each module of the HPLC system. While each company's procedure might differ in the details, most share these common strategies. 77

By Whom: An analyst, a metrologist, or a qualified contractor can perform the calibration, though all must follow the company's prescribed standard operating procedure (SOP) and acceptance criteria. The cost effectiveness of using outside contractors or an internal metrology department is dependent on company size and the number of HPLC systems in the laboratory.77 When: Most HPLC systems in pharmaceutical laboratories are calibrated every 6-12 months. The calibration gaps longer than 12 months are not recommended. And, the gaps shorter than 3 months are deemed unnecessary, because each HPLC system is also subjected to a daily system suitability check to ensure sufficiency for the application.

100

A REVIEW ON PHARMACEUTICAL VALIDATION How A list of common strategies in selecting calibration procedure and adopting acceptance criteria is given below: 1. Annual preventive maintenance, in which most wearable items such as pistons, seals, lamps, and filters are replaced, is to be scheduled before calibration. 2. Before calibration, each module is shut down and powered-up to evoke built-in diagnostics for detecting problem situations. 3. The calibration order is: detector ~ pump ~ auto sampler (as the detector is often used to calibrate other modules). 4. Common performance characteristics to be verified for each module are: UV detector

: Wavelength accuracy, absorbance linearity, and sensitivity;

Pump

: Flow rate accuracy and precision, and compositional accuracy;

Auto sampler : Sampling precision and accuracy; Oven

: Temperature accuracy;

Overall system: System dwell volume and instrumental bandwidth. 5. Acceptance criteria generally mirror the manufacturer's specifications though many are necessarily relaxed to accommodate diversified models and aging components. 6. The calibration standard employed should be National Institute of Standards and Technology (NIST) traceable and easily obtainable.77

Validation program Overview in Picture:

Figure 7: Schematic diagram showing the overall validation strategy 101

A REVIEW ON PHARMACEUTICAL VALIDATION HPLC Chromatography Calibration Procedure Check HPLC chromatography (Pump) for the following: I. Check point: Leakage test (By Pressure Drop) II. Flow rate calibration

Check point: Leakage test (By pressure drop) 1. Ensure that, the instrument is ready for calibration and Start-up procedure is followed. 2. Place inlet tubing of the Pump in to the Water HPLC grade through suction filter. 3. Allow mobile phase to flow for about 5 min. 4. Block Pump outlet with the block screw. 5. The pressure rises and on crossing the 300 bar, ―ERROR P-MAX‖ appears on the display window. Note the time. Press ―CE‖ key and observe the pressure drop for 5 min. 6. After 5 min., record the pressure in calibration Log. 7. Make entry of the column usage in the Column Usage Log Register. 8. Make entry of the usage in to the Instrument Usage Log Register. 9. Compare the result for its compliance against limit given in the Calibration Log and put the remark regarding the HPLC chromatography Calibration Status. 10. In case of non-compliance, follow the Maintenance Program.80

Flow rate calibration 1. Ensure that, the instrument is ready for calibration and Start-up procedure is followed. 2. Ensure that, the Pump is passing the ―Leakage Test (By Pressure Drop)‖. 3. Keep the Drain tube in such a way that the mobile phase (Water) drops falls in to 10 ml clean, dry volumetric flask without touching the walls of the flask and start immediately the stopwatch when first drop falls in to the flask. 4. Wait till the collected mobile phase reaches 10 ml mark of the volumetric flask and Stop the stopwatch. . 5. Record the time required to collect the 10 ml mobile phase in calibration Log. 6. Repeat the procedure for 1.0 ml, 1.5 ml and 2.0 ml/ min. flow rates. 7. Repeat the step 3 to 6 but using Methanol HPLC grade as mobile phase instead of water.

102

A REVIEW ON PHARMACEUTICAL VALIDATION 8. Compare the results for its compliance against limits given in the Calibration Log and put the remark regarding the Calibration Status. 9. Make entry of the usage of the instrument and column in the Instrument Usage Log Register and Column Usage Log Register respectively. 10. Prepare Calibration Status Label and display on the instrument at the designated place. 11. In case of non-compliance, follow the Maintenance Program.78 Calibration Parameters of HPLC: 1. Flow rate capacity 2. Injector accuracy 3. System Precision 4. Wavelength Accuracy 5. Detector linearity 6. Injector linearity 7. Gradient performance check 8. Column oven temperature accuracy

1. Flow rate Accuracy: 

Run all the solvent lines with Milli Q water (i.e. HPLC grade water).



Set the flow rate 0.500ml/min.



Wait for about 15 min to stabilize the system and ensures that the pressure is stable.



Insert the outlet tubing into a 10 ml volumetric flask and start stop watch simultaneously.



Stop the stopwatch when the lower meniscus reaches the 10 ml mark on the flask.



Record the elapsed time.



Similarly, check the flow for 1.0ml/min and 2.0ml/min

Acceptance criteria: The time taken to collect the water should be within 2.0% of the actual value.79 2. Injector Accuracy: 

Connect the pump and detect inlet with union.



Prepare mobile phase consisting of a mixture of water and methanol.



Set a flow rate of 0.5ml/min and run time of 1 min. 103

A REVIEW ON PHARMACEUTICAL VALIDATION 

Set the column temperature at 25(+/-) 2 o c.



Fill a standard HPLC vial to 2/3 rd with water. Seal the vial properly with a cap.



Weigh the vial and record the weigh as W1 grams.



Place the vial in the chromatographic system and perform 6 injections of 50 microlitre volume from this vial.



Weigh the vial again and note the weigh after injection As W2 grams.

Calculate the mean volume injected per injection as follows: Mean injected volume :( w1-w2)*100/6. Acceptance Criteria: the mean injected volume should be 50.0(+/-) 1.0 microlitre.79 3. System precision: Standard preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml volumetric flask. Dissolve and dilute to the volume with mobile phase. Transfer 10 ml of this solution into a 100ml volumetric flask and dilute to the volume with mobile phase. Procedure: Inject blank, followed by standard preparation in 6 replicates. Note down the areas and retention times. Now calculate the% RSD of retention time and peak areas for 6 replicates injection. Acceptance Criteria: The % RSD of retention time and peak area should be less than 1.0% 4. Wavelength Accuracy: Procedure: Create and instrument method with a wavelength in nm and inject blank, followed by standard preparation and note down the height or absorbance. Acceptance criteria: the maximum absorbance should be at (+or -) 2nm. 5. Detector Accuracy: Select 3d mode and set the wavelength ranges 200-400nm. Inject 20 microlitre of standards preparation once into the chromatographic system. Extract and record the chromatographic at wavelength of 202 to 208 nm with an interval of 1 nm to 269 to 275 nm with an interval of 1nm. Note down the height or absorbance. Acceptance Criteria: The maximum absorbance should be at 205(+/-) 2 nm and 272(+/-) 2nm. Standard preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml volumetric flask. Dissolve and dilute to the volume with mobile phase. Now prepare the following solution: 

Detector linearity solution 1 (0.06mg/ml) 104

A REVIEW ON PHARMACEUTICAL VALIDATION 

Detector linearity solution 2 (0.048mg/ml)



Detector linearity solution 3 (0.03mg/ml)



Detector linearity solution 4 (0.24mg/ml)



Detector linearity solution 5 (0.012mg/ml)

Procedure: Inject blank, followed by detector linearity solutions and record the peak response of caffeine standard plot between the concentration vs the peak responses. Acceptance criteria: The plot should be linear and regression coefficient should not be less than 0.99. 6. Injector linearity: Standard Preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml volumetric flask. Dissolve and dilute to the volume with mobile phase. Transfer 10 ml of standard preparation into a 100ml volumetric flask and dilute to the volume with mobile phase. Procedure: Inject 5 microlitre of the mobile phase as blank injection. Inject 5, 10, 20,50and 80 microlitre of the standard preparation and record the peak areas. Plot a curve for the volume injected vs peak area. Acceptance criteria: The plot should be linear and regression coefficient should not be less than 0.99. 7. Gradient performance check: Add 5ml of acetone to 1000 ml of methanol filter and degas. Connect the pump and detector inlet with union. Set the detector wave length at 254 nm. Place channels A and C in methanol and channel B and D in 0.5% acetone in methanol. Set gradient program as show below for channels A, B, C and d individually Acceptance criteria: The calculated percentage composition should be within 1.0% of the set composition. 8. Column oven temperature accuracy It is evaluated with a calibrated digital thermometer at 30 0c and 60°C.Place and thermometer probe in the column oven and set the column oven temperature at 30 °C. Wait till the temperature stabilizes. Record the temperature displayed on the thermometer. Similarly performs the column oven temperature accuracy test at 60 °C. Acceptance criteria: The resulting oven temperature from the thermometer display should be within 2°C of the set temperature. 105

A REVIEW ON PHARMACEUTICAL VALIDATION Summary of Calibration Tests and Acceptance Criteria80 Test

Procedure

Detector

Wavelength

Maximum absorbance of anthracene 251_+3 nm

PDA or

accuracy

solution (1 g/mL).

Flow accuracy

Run pump at 0.3 and 1.5 mL/min < + 5%

HPLC

Acceptance Criteria

module

340_+ 3 nm 2

UV/Vis Pump

(65%acetonitrile/water) and collect 5 mL from detector into a volumetric flask. Measure time. Compositional

Test all solvent lines at 2 mL/min with 1% absolute

accuracy

0.1% acetone/water, step gradients at 0%, 10%, 50%, 90% and 100%. Measure peak heights of respective step relative to 100% step.

Column

Temperature

Check actual column oven temperature 35+/-2"C

Oven

Accuracy

with validated thermal probe.

Auto

Precision

Determine the peak area RSD of10-1uL RSD 0.999 correlation of one injection of 5-, 10-, 40and

80-microlitre

of

ethylparaben

solution.

106

A REVIEW ON PHARMACEUTICAL VALIDATION 3.5.9 HVAC Validation HVAC is the abbreviated form of - Heating, Ventilating and Air Conditioning which is a system, which provides conditioned air by providing Heating, Cooling & Ventilation. HVAC system plays an important role in product, personnel, environment, instruments and machine protection. HVAC utility is designed to control the level of viable and non-viable particulate exposure that a drug or medicinal device might receive in addition to regulating temperature and relative humidity conditions. It is qualified to demonstrate operating conditions of the area. The areas serviced by the HVAC utility are classified based on viable and non-viable particulate levels during static operating conditions and dynamic operating conditions.81 The parameters of HVAC include the following: 

Temperature



Relative Humidity



Air Class



Room to room Pressure Gradient



Air Quality



Sound level.

Recommended limit of the above HVAC Parameters are mentioned below: 

Temperature: 20±5ºC



Relative Humidity: It is recommended to maintain RH within 50±5 % in all manufacturing areas, unless there is any specific recommendation for any special operation. For example, for Effervescent product manufacturing it is recommended to maintain the relative humidity around 20%.



Air Class: As per International standards; i.e. Federal standards, ISO standards; British standards etc.



Pressure Gradient: It should be maintain relatively negative unless there is any special requirements. E.g. For sterile areas.



Air Quality: It should be Dust and Odor free.



Sound level: It should be maintained within 20 db.

107

A REVIEW ON PHARMACEUTICAL VALIDATION 

Pharmaceutical rules and specifications are often contains very precise but also generally formulated requirements of air conditioning technology such as temperature, humidity and ventilation of premises should be adequate.

Two basic types are distinguished by the terms of 

Room Ventilation Technology and



Process Air Conditioning Technology.

Both types are found and required in the pharmaceutical manufacturing sites. The essential task of a ventilation system is to guarantee that the desired room conditions such as temperature, humidity and cleanliness. In contrast, the process air systems must guarantee the required process parameters.

Quality standards: The HVAC system must supply quality air which should be in compliance to all standards according to: 

ISO EN 14644.5:2004: Clean room and associated controlled environments, part 5: clean room operations



PIC/S Guideline to GMP for medicinal product



ISPE Baseline guide volume 3, sterile manufacturing facility



AS 1386.31989 Clean rooms and clean workstation part 1&3



EU GMP Guide, Volume IV GMP for medicinal products section 3 premises and equipment



21CFR part 11 Subpart C building and facility and subpart D



United States Pharmacopeia USP 32



European Pharmacopeia Ph Euro 7th Edition



ISO/IEC 17025 General requirements for the competence and testing of calibration and testing laboratories.57

System boundaries: The physical boundaries are defined as follows: 

Source of air handling units (AHUs) and air conditioning units (ACUs) including other forms of air pretreatment (e.g., heating/cooling, dehumidification/ humidification).

108

A REVIEW ON PHARMACEUTICAL VALIDATION 

AHUs require externally supplied heating and cooling sources such as steam, hot water or chilled water.



ACUs are self-contained with respect to heating and cooling and generally employ a refrigeration-based heat pump. They may be reversible and both heat and cool the supply airflow.



AHUs, ACUs and associated ductwork, which supply air to critical and controlled areas/rooms are included while AHUs, ACUs and related ductwork, which supply non-GMP; uncontrolled areas (e.g. offices, cafeterias) are not included.



Supply air and return air ductwork up to but not including grills inside rooms or areas.



Support utility interfaces (e.g. electrical connections at disconnect points) for heating/cooling water supplies etc.82

Area Description: This area is defined to use only sterile oriented products for manufacturing. The aseptic process involves the handling of sterile components until they are sealed in their final containers. Aseptic area is designed, constructed and engineered to comply with pharmaceutical compliance standards and to prevent microbial contamination.58 The clean room for the aseptic area is classified according to the required characteristics of the environment in four ways, such as: A. Federal Standard B. British Standard C. ISO standard D. EU CGMP

109

A REVIEW ON PHARMACEUTICAL VALIDATION A. Table: Federal Standard 209E, Clean room classification

B.Table: British Standard 5295:1989

110

A REVIEW ON PHARMACEUTICAL VALIDATION C. ISO airborne particulate cleanliness classes Class

maximum number of particles In each cubic meter equal to or greater than the specified size 0.1µm

0.2µm

0.3µm

0.5µm

ISO 1

10

2

ISO 2

100

ISO 3

1µm

5µm

24

10

4

1000

237

102

35

8

ISO 4

10000

2370

1020

352

83

ISO 5

100000

23700

10200

3520

832

29

ISO 6

1000000

237000

102000

35200

8320

293

ISO 7

352000

83200

2930

ISO 8

3520000

832000

29300

ISO 9

35200000

8320000

293000

D. Table: According to EU cGMP Grade

At Rest(b)

In Operation(b)

Maximum permitted number of particles/m3 equal to or above(a) 0.5μm(d)

5μm

0.5μm(d)

5μm

A

3,520

20

3,500

20

B(c)

3,520

29

35,000

2,900

C(c)

35,200

2,900

352,000

29,000

D(c)

3,520,000

29,000

Not defined(f)

Not defined(f)

111

A REVIEW ON PHARMACEUTICAL VALIDATION The ―in-operation‖ and ―at rest‖ states should be defined for each clean room or suites as mentioned in the below-mentioned grade:

Grade A: The local zone for high-risk operations includes aseptic filling zone, stopper bowls, open vials and making aseptic connections. This zone is equipped with laminar flow systems with homogenous air speed in a range of 0.36 to 0.54m/s. Grade B: This is the background environment for grade A zone. Grade C: This is the clean areas for carrying out less critical processes in the manufacture of sterile products. Grade D: This area is unclassified as it is meant for capping gowning room and black/grey change room.

Cleanliness Phase:

Cleanliness grade A (FS 209 E class 100 at rest) ISO 5 US class 100 in operation SI M* 3.5



The local zone for operations with a high level of risk, for example in the filling area, assembly of the filling apparatus (pump, filter, etc.), aseptic connections (equipment, tubes, couplings) under laminar airflow of 0.45 m/s, 20%.  Microbiological limit