Pharmaceutical Validation PDF

Pharmaceutical Validation Definition On March 29, 1983 draft on guidelines entitled "Guidelines on General Principles of Process Validation" was made available and the same was finalized in May, 1987. The finalized definition was as follows: "A documented program, which provides a high d...

Pharmaceutical Validation Definition On March 29, 1983 draft on guidelines entitled "Guidelines on General Principles of Process Validation" was made available and the same was finalized in May, 1987. The finalized definition was as follows: "A documented program, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes". Scope of Validation Pharmaceutical Validation is a vast area of work and it practically covers every aspect of pharmaceutical processing activities. A systematic look at the pharmaceutical operations will point out at least the following areas for pharmaceutical validation. e.g. 1. Buildings and Facilities. 2. Equipment. 3. Analytical Test Methods. 4. Manufacturing operations (Process validation). 5. Cleaning. 6. Instrument Calibration. 7. Process Utility services. 8. Raw materials. 9. Packaging materials. 10. Product Design. 11. Operators. Importance of Validation 1. Assurance of quality: We must remember that, end-product testing, in the absence of validated processes, gives little assurance of quality. So validation and process control are at the heart of quality assurance and GMPs. Without validated and controlled processes, it is impossible to produce quality products consistently. 2. Reduction of Quality costs: Validation reduces the costs associated with the internal failure (e.g. rejects, retesting) and/or external failure (e.g. recalls, complaints). 3. Increased operational safety: Calibration of instruments assure their reliability and safe use e.g. gauges used on equipment that is designed to operate at certain temperatures and pressures must be reliable i.e. they must be calibrated. Organization for Validation Validation activity is not the responsibility of any one single department in an organization. The organization must have a group of people pulled from various departments and convert it into a good homogeneous team. The team members may be taken from R&D, Quality, Production and Engineering. Validation of Buildings and Facilities Validation of Buildings and Facilities may be defined as "Obtaining and documenting evidence to demonstrate that the buildings and facilities can be relied upon to produce the specified environmental conditions within pre defined limits". So far as, Validation of the buildings and facilities is concerned, it should be treated similar to equipment validation. In other words, the buildings and facilities should have following five documents regarding validation e.g. 1. User Requirement specification (URS). 2. Design Qualification (DQ). 3. Installation Qualification (IQ). 4. Operational Qualification (OQ). 5. Performance Qualification (PQ). Validation of Buildings and Facilities User Requirement Specifications (URS): URS for buildings and facilities is a statement spelling out, what the user wants in terms of the buildings and facilities (expectations/ requirements) for the manufacture of the pharmaceutical formulations. It can be expressed in the following manner. (i) The facility will be used for the manufacture of the following formulations and volumes, namely: (a) Tablets - coated 10L/shift (b) Tablets - uncoated 20L/shift (c) Tablets - Hard gelatin capsule 5L/shift (d) Tablets - Small volume parenterals 50K Ampoules/shift (e) Tablets - Large volume parenterals 20K bottles of 500 ml/shift (f) Tablets - Ointments/ Cream 20K tubes of 10g/shift (ii) The facility will handle the following categories of products e.g. - β- Lactam products - Steroids - Vaccines - General pharmaceutical products etc. (iii) The facility should have the following provisions: - Manufacturing facility. - Warehousing facility. - QC/ R&D Lab./ Pilot plant. - Utility block. - Car parking/cycle parking. - Security office. - Change rooms, canteens etc. Validation of Buildings and Facilities Design Qualification (DQ): Design Qualification may be considered as the total building and facility specifications which are approved and finalized by the authorized persons (team) of the client. The team consists of qualified and authorized persons from Production, Engineering, Project, Quality Management, etc. DQ spells out many specifications such as: location and size of facilities, types and volumes of proposed formulations, equipment places, HVAC system, classes of air, temperature, humidity, sound levels, storage areas, segregation/ grouping of areas, cleaning, sanitation and maintenance of buildings details, plot drawing with dimensions and layouts, doors, windows, surface finish, men- material movement charts, compressed air, vacuum, steams, electric powers, drainage, etc. Validation of Buildings and Facilities Installation Qualification (IQ): Installation Qualification should refer to the validation of the finished empty premises. The IQ of premises in general involves verification of the following things at the minimum as specified in the DQ. 1. Size verifications of each room, corridors, etc. 2. Surface finishes of the flooring, walls, ceilings, etc. 3. Ease of cleaning, maintenance and operation as detailed out in DQ. 4. Installed HVAC in place. 5. Terminal HEPA filters are in place. 6. Environmental Air System. 7. Verification of lighting intensity as per the nature of the job involved. 8. Limits of sound in the working area. 9. Floor drainage system. 10. Plumbing. 11. Sewage and trash collection, storage and disposition. 12. Washing and toilet facilities. 13. Building and building surroundings sanitation and maintenance etc. Validation of Buildings and Facilities Operational Qualification (OQ): Operational Qualification refers to validation of equipped but non- operational premises. This is important in order to determine the air flow pattern in the critical areas associated with the processing equipment, lighting and sound levels should also be carried out. This should be done mainly to see if there is any problem related to lighting, drainage, men and material movements, sewage and trash management, sanitation, cleaning and maintenance. If you face any problem in any of the above areas because of the installation of the equipment then necessary corrective actions should be taken. Validation of Buildings and Facilities Performance Qualification (PQ): Performance Qualification refers to validation of fully equipped and operational premises. This validation will show us the total environmental quality with all the influencing factors present. This means to evaluate the premises suitability with equipment in operation, materials being handled, people are working, various sounds are being produced, dust is getting generated, exhaust systems are operating, spillages may be occurring, heat is getting generated, filters getting choked and so on. Validation of Equipment Equipment is one of the basic components of the pharma processing and hence, a critical validation is also important. The equipment validation process generally covers the following steps. a. Customer Requirements or User Requirement Specification (URS). b. Preparation of Design Qualification (DQ) and its Certification. c. Installation Qualification (IQ). d. Operational Qualification (OQ). e. Performance Qualification (PQ). Validation of Equipment a. Customer Requirements (User Requirement Specifications (URS)): Customer or the user of the equipment has certain expectations about the equipment which he wants to use. These expectations are generally put in the form of his requirements. These requirements are generally discussed with the equipment manufacturers or suppliers and based on this discussion the selection of the equipment is done. The equipment manufacturer then prepares the design qualification (DQ) report and sends it to the user for approval. Some of the general requirements may be stated in the form of certain parameters like: 1. Size of the equipment. 2. Speed of the equipment. 3. Ease of operation, cleaning and maintenance. 4. Materials of construction. Validation of Equipment b. Preparation of Design Qualification (DQ) and its Certification: If a particular equipment is to be fabricated as per our requirements (URS) then the detailed design qualification (DQ) document become very important and essential. DQ is prepared by the manufacturer. Once this is ready, it should be agreeable to both the parties i.e. purchaser and manufacturer. Generally, the Factory Acceptance Test (FAT) is performed at the manufacturer's premises before dispatch of the equipment to the purchaser. Validation of Equipment c. Installation Qualification (IQ): Installation Qualification may be defined as "Documented Verification that all key aspects of the installation adhere to manufacturer's recommendation, appropriate codes and approved design qualification". The simple meaning of this statement is that the equipment in question can be installed when it is qualified for installation; i.e. when it passes the IQ Test. d. Operational Qualification (OQ): Operational Qualification may be defined as "Documented Verification that the system or subsystem performs as intended throughout all specified operating range". The equipment should be operated only when it passes the OQ test. e. Performance Qualification (PQ): Performance Qualification is considered by many as synonymous with OQ. Some experts consider OQ as verification of performance of the system or subsystem without load and PQ is the same with load. Process Validation Process Validation (PV) may be defined as – "a documented program which provides a high degree of assurance that a specific process will consistently produce a product, meeting its pre- determined specifications and quality attributes". Process validation starts only after the complete qualification program (DQ, IQ, OQ, PQ) of facilities and equipment is over. Process validation can be categorized in the following categories namely: (a) Prospective validation. (b) Concurrent validation. (c) Revalidation. (d) Retrospective validation. Now let us briefly look at each of these. Process Validation Prospective Validation: Prospective validation means validation, which is done during the product development stage. When we develop a new manufacturing process each step in the new process is required to be established that it will give us the desired results, in the routine processing. During this, the input resources are selected and clearly specified, e.g. material specifications are defined, equipment and process parameters are defined, operating condition if any are specified. That means a profile of all inputs and operating parameters both are decided and recorded. Then with these specifications the output is studied and the specifications of the output is defined and shown by repeated experiments that they are consistent. Process Validation In this phase the limits of variations of the process parameters are identified and it is shown that within these variation the output product will still be within the quality specification defined. The laboratory batch is then scaled up-to pilot batch, which may be about 10 times bigger than this and again the same exercise of evaluation at that scale is carried out and specifications of inputs, parameter limits of the process and quality specifications in the final output are verified and finalized. The actual commercial batches can be scaled up-to 10 times of the pilot batch. At least first 3 commercial batches on commercial scales are then taken along with the production personnel and all specifications and parameters limits are finalized and the product is then handed over to manufacturing. Process Validation Concurrent Validation: Concurrent validation is the validation, which is carried out during production. If initial development batches and the commercial production batches use same type of equipment then concurrent validation of the whole process during commercial manufacturing may not be required. However only IPQC tests at critical stages may only be enough. But generally the equipment, plant and machinery used in developmental batches and commercial batches are different, because of scale of operation, a full validation using commercial production equipment is recommended. IPQC and validation co-exist in GMP or QA system. Process Validation Revalidation: Validation of a process is a once-off procedure that should only be repeated if major changes to equipment or processes have taken place. Revalidation is as a rule required under the following circumstances:  Change of formulae, equipment, procedures or quality of raw materials. e.g. even physical variation of raw materials like, bulk density, particle size, etc. may require revalidating the process.  Changes to facilities and installations which influence the process. Process Validation Retrospective Validation: Retrospective validation may be defined as, "establishing documented evidence that a system does what it purports to do based on a review and analysis of historical data and information obtained during production of clinical or marketable product". Retrospective process validation may be used, if adequate, for products which may have been on the market without sufficient pre- production process validation. Retrospective validation may be allowed, when the formulation procedure and equipment have not been altered. A critical examination of the in process control IPQC data and of the analytical results should be performed. Where existing data if not adequate, additional tests should be performed. Validation of Analytical Methods Definition: Validation of Analytical method may be defined as "The process by, which it is established, by laboratory studies, that the performance characteristics of the analytical method meet the requirements for the intended analytical application". Typical analytical characteristics can be listed as follows. 1. Accuracy 2. Precision 3. Specificity 4. Limit of Detection 5. Limit of Quantitation 6. Linearity 7. Range 8. Ruggedness 9. Robustness. Validation of Analytical Methods Accuracy: Definition: "The closeness of test results obtained by that method to the true value. This accuracy should be established across its range." Accuracy of an analytical method may be determined by the assay method used on a highly pure substance like reference standards and compared it with the same material with a known and established method. Accuracy is calculated on the percentage of recovery by the assay of the known added amount of analyte in the sample. The ICH recommends that the accuracy should be assessed using a minimum of 9 determinations over a minimum of 3 concentration levels, covering the specified range (i.e. 3 concentration and 3 replicates of each concentration). In case of quantitative analysis of impurities, accuracy should be assessed on samples of drug substance or product by spiking with known amounts of impurities. This type of spiking technique can also be used for formulated drug products. Validation of Analytical Methods Precision: Definition: "The degree of agreement among individual test results when the method is applied repeatedly to multiple sampling of a homogenous sample". Precision refers to degree of reproducibility of results. This can be within a single laboratory or between more than one laboratories. Precision can also be considered as repeatability of results, which refers to comparison of results of an analysis within a short time by the same analyst, in same laboratory and using the same equipment. The ICH documents recommend that repeatability should be assessed using a minimum of 9 determinations covering the specified range for the procedure (i.e. 3 concentrations and 3 replicates of each concentration). The precision of an analytical method is usually expressed as the standard deviation (SD) or relative standard deviation (RSD) (i.e. coefficient of variation, CV) of a series of measurement. Validation of Analytical Methods Specificity: Definition: Specificity may be defined as "The ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities degradation products and matrix components". Specificity can be used for identification tests, purity tests, assays, etc. The ICH documents state that, when chromatographic procedures are used, representative chromatogram should be represented to demonstrate the degree of specificity (selectivity) and peaks should be appropriately labelled. Validation of Analytical Methods Limit of Detection: Definition: The limit of Detection may be defined as "The lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions". The LOD is generally expressed as the concentration of the analyte sample (e.g. percentage or parts per million, etc.). The ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analytes with those of blank samples. These detection limits should be subsequently validated by the analysis of a suitable number of samples of known to be near or prepared at the detection limit. Validation of Analytical Methods Limit of Quantitation: Definition: LOQ May be defined as "A characteristic of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions". The LOQ is generally expressed as the concentration of the analyte in the sample (e.g. Percentage or parts per million, etc.). The ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analytes with those of blank samples. These quantitation limits should be subsequently validated by the analysis of a suitable number of samples known to be near or prepared at the quantitation limit. Validation of Analytical Methods LOD is the smallest concentration of an analyte in a test sample that we can easily distinguish from zero. LOQ is the smallest concentration of an analyte in a test sample that we can determine with acceptable repeatability and accuracy. Validation of Analytical Methods Linearity: Definition: The Linearity of an analytical method may be defined as "Its ability to elicit tests that are directly or by a well defined mathematical transformations proportional to the concentration of analyte in samples within a given range". It should be established initially by visual examination of a plot of signals as a function of analyte concentration of contact. If this appears to be a linear relationship, test results should be established by appropriate statistical methods like regression analysis, etc. ICH Recommends that, for the establishment of Linearity, a minimum of 5 concentrations normally be used. Validation of Analytical Methods Range: Definition: The range of an analytical method may be defined as "Interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy and linearity using the method as written. The range is normally expressed in the same units as test results. (e.g. Percentage, parts per million, etc.) obtained by the analytical method. Validation of Analytical Methods Ruggedness: Definition: The Ruggedness of an analytical method may be defined as "The degree of reproducibility of test results obtained by the analysis of the same sample under a variety of conditions such as different laboratories, different analysts, different instruments, different lots of reagents, different elapsed assay times, different assay temperatures, different days, etc." Ruggedness is normally expressed as the lack of influence of operational environmental variables of the analytical methods on test results. Ruggedness is a measure of reproducibility of test results under the variation in conditions normally expected from Laboratory to Laboratory and analyst to analyst (i.e. variation of environmental conditions that may differ but are still within the specified parameters of the assay). This reproducibility may be compared to the precision of the assay under normal conditions to obtain a measure of the ruggedness of the analytical method. Validation of Analytical Methods Robustness: Definition: The robustness of an analytical method may be defined as "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". Cleaning Validation Cleaning and decontamination is one of the major and critical activity in pharmaceutical operations. The four basic requirements of cGMP are identity, safety, strength and purity. The concept of purity and safety are directly related to the cleaning operations. Dependency on the cleaning procedures for achieving the desired level of cleanliness primarily depends upon the validity of the method of cleanliness. When we talk about cleanliness and cleaning validation, we mainly refer to the equipment, utensils and facilities used in the pharmaceutical processing. There are different levels or degrees of cleanliness required in pharmaceutical operations and naturally the specifications for each of the cleaning will differ substantially. Cleaning Validation Cleaning Validation may be defined as "a process of attaining and documenting sufficient evidence to give reasonable assurance, given the current state of Science and Technology, that the cleaning process under consideration does, and/ or will do, what it purports to do”. The cleaning validation will involve addressing of some basic issues like: - What equipment and areas are involved? - What are the materials of construction (MOC) of the equipment and surfaces in the facility require cleaning? - What cleaning agents are being used and in what concentration? - What is the degree of cleaning expected and above all how is one going to achieve this level of cleanliness repeatedly. All this makes the cleaning validation a complex, critical and vital activity in pharmaceutical processing. Cleaning Validation CFR 211.67 on Cleaning CFR 211.67 spells out following requirements regarding cleaning and cleaning validation. a. Equipment and utensils shall be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements. Cleaning Validation b. Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: Assignment of responsibility for cleaning and maintaining equipment. Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules. A description in sufficient details of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance. Protection of cleaned equipment from contamination prior to use. Inspection of equipment for cleanliness immediately before use. Validation Master Plan Definition: Validation Master Plan is an internally approved document that describes, in clear and concise wording, the general expectations, intentions, methods and approach to be used during the entire validation effort. Legal Requirement:  Now here it is said that the Validation Master Plan is required by law.  The FDA inspectors do demand a copy of the Validation Master Plan to see.  The idea of this document is to show the FDA inspectors that the company has a highly organized approach to the Validation Program. Validation Master Plan Usually the VMP should cover the following areas e.g.  Introduction to the proposed validation program.  Validation of buildings and facilities.  Validation of equipment used in production and utilities.  Pharmaceutical process validation.  Analytical methods and analytical instrument validation.  Cleaning validation.  Water system.  HVAC system  Vendor certification  R.M./P.M. specifications. Validation Master Plan Advantages of Validation Master Plan: It provides to all the concerned people and also the FDA inspectors, the complete scope of the activities planned to be performed in the organization. The scope of the activities makes following points clear:  What activities are to be performed?  Who is going to perform these activities?  When the activities should start and when they should get over? (Time frame of activities.)  How the activities will be performed?  What documents will be generated? (Delivered by Validation Department to the management.)  What is the policy on revalidation?  Who are the authorized persons to initiate and review the validation activities, etc.? Conclusively it can be said that a VMP should be a reflecting mirror of your good intentions in the area of your planned work on validation. Validation Master Plan Starting Point for Validation Master Plan: Validation Master Plan should be started as early as possible, in case of new pharmaceutical plants. It should be reviewed and revised at a definite time frequency preferably once a year.