Pharmaceutical Process validation


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Pharmaceutical process validation

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Pharmaceutical Process validation

  1. 1. VALIDATION Process 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 characteristics. Rakesh Kumar Sharma 1/20/2014 1
  2. 2. Planning for validation Validation activities can be organized by preparing the validation master plan (VMP). It should be brief, concise and clear. The EEC guide recommends the following contents in a VMP. Validation Policy Organizational structure of validation activities. Summary of facilities, systems, equipment and processes to be validated. Documentation format Planning and scheduling Change control Reference to exiting documents. Rakesh Kumar Sharma 1/20/2014 2
  3. 3. Process validation work in a pharmaceutical industry can be organized in one of the three structures; The consultant The task force The dedicated group Rakesh Kumar Sharma 1/20/2014 3
  4. 4. The consultant: The consultant are the group of persons which are hired by the company for a specific job. They can immediately review processes and present protocol for validation. They can take advantage of experience gained in other companies to solve the problem in lesser time than the company’s men. They are not the permanent employees of the company and it may be advantageous to the company. If the validation job is not completed within agreed time and costs, the company may be left with an incomplete job. The consultant should be hired after careful consideration of time and money. Rakesh Kumar Sharma 1/20/2014 4
  5. 5. The Task force: The task force concept refers to an organization approach in which persons from various divisions of the company are selected and assigned validation work. Usually persons from production, engineering, quality assurance and validation work. These persons meet as a committee. The head of this committee, leader of the task force is the person responsible for validation work and documentation. Rakesh Kumar Sharma 1/20/2014 5
  6. 6. The major advantages of this structure are: When the job is complete they can return back full time to their previous assignments. Some of the members of the task force can be replaced with others depending upon the work to be tackled. Rakesh Kumar Sharma 1/20/2014 6
  7. 7. The Dedicated group The dedicated group describes a set of persons whose principle assignment is validation work. They work autonomous. The advantage of this structure is that this group is totally dedicated and responsible for validation work. As such there is no conflict of interest. Rakesh Kumar Sharma 1/20/2014 7
  8. 8. Process characterization: To find out critical process parameters, process characterization and process ranging studies should be carried out. Methods used to find out the critical processing steps and process control variables that affect the quality and consistency of the product attributes constitute process characterization. Studies used to identify the critical process and their respective control limits affecting the quality and consistency of the product attributes constitute process ranging. Rakesh Kumar Sharma 1/20/2014 8
  9. 9. The process characterization techniques that may be used to designate the critical unit operations in the manufacturing process are:Cause and Effect or fishbone diagram: There may exist different relationships and interrelationships among various process variables (causes) and single response or product attribute (effect). This can be represented by a fishbone diagram. Rakesh Kumar Sharma 1/20/2014 9
  10. 10. After having decided the structure of the team for validation, it is advisable to make a list of categories of the products that should be validated in order of priority. A list which may be used as guideline is given below. Large volume Parenterals Small volume parenterals Ophthalmics and sterile solids. Tablets and capsules Oral liquids and topical. Rakesh Kumar Sharma 1/20/2014 10
  11. 11. A fishbone diagram of the processing steps and inprocess variables during Tablet Manufacture is given below. Rakesh Kumar Sharma 1/20/2014 11
  12. 12. Branches of the central line represent the influence of process steps. Process variables of process steps have been represented by sub branches. To find out the effect of the process variable, it is varied in a measured way within operating ranges. If there is no effect on final outcome, the input variable is considered noncritical variable and that which influence the final outcome are considered critical. Rakesh Kumar Sharma 1/20/2014 12
  13. 13. Rakesh Kumar Sharma 1/20/2014 13
  14. 14. Constraint analysis: Application of constraint analysis makes evaluation and performance qualification trials manageable. In this constrain the number of process variables and product attributes that require analysis, similarly application of constrain analysis will also limit and restrict the operational range of each process variable and or the specification limits of each product attribute. Rakesh Kumar Sharma 1/20/2014 14
  15. 15. Information comes from the following source for constraining process variables. Previous experience with related product and processes, processing equipment, etc. In practice, pareto principle or 80-20 rule can be used. The pareto rule states that about 80% of the variation in the process output is caused by only about 20% of all the input process variable. Rakesh Kumar Sharma 1/20/2014 15
  16. 16. Validation protocol After preparing VMP, the next step is to prepare validation protocol. There are at least the following contents in a validation protocol. Purpose and scope of validation Responsibilities and functioning of persons units involved in the validation. Type of validation to be conducted Number of process validation runs. Quality of materials used in the process Rakesh Kumar Sharma 1/20/2014 16
  17. 17. Description of the process All major equipment to be used, their IQ and OQ. Critical process parameters and operating ranges. Sampling plans Specifications and test data to be collected. Acceptance criteria to conclude that validation has been successful. Measures to be taken in the event of process validation failure. Rakesh Kumar Sharma 1/20/2014 17
  18. 18. Pre-requisites of Validation (Facilities, Systems and Equipment) Qualification is pre-requisite of validation. The qualification includes the followings. Design qualification [DQ]: In this qualification, compliance of design with GMP should be demonstrated. The principles of design should such as to achieve the objectives of GMP with regards to equipment. Rakesh Kumar Sharma 1/20/2014 18
  19. 19. Installation qualification [IQ]: Installation qualification should be carried out on new or modified facilities, systems and equipment. The following points should be included in the installation qualification. Checking of installation of equipment, piping, service and instrumentation. . Rakesh Kumar Sharma 1/20/2014 19
  20. 20. Collecting of supplier’s operating working instructions and maintenance and their calibration requirement. Verification of material(s) of construction Source of spares and maintenance Rakesh Kumar Sharma 1/20/2014 20
  21. 21. Operational qualification [OQ]: OQ should follow IQ. OQ should include the following Test(s) developed from the knowledge of the process(s), system(s) and equipment. Defining lower and upper operating limits. Rakesh Kumar Sharma 1/20/2014 21
  22. 22. Completion of OQ will result in finalization of Calibration Operating and cleaning procedure Operator’s training Maintance requirements Formal release of the facilities, systems and equipment. Rakesh Kumar Sharma 1/20/2014 22
  23. 23. Performance Qualification [PQ]: After IQ and OQ have been completed, the next qualification that should be completed is PQ. PQ should include the following Test using production materials, substitutes or simulated products. These can be developed from the knowledge of the process and facilities, system or equipment. Rakesh Kumar Sharma 1/20/2014 23
  24. 24. Tests to include conditions(s) with upper and lower limits. It will be useful to discuss briefly process capability design and testing and process qualification. Rakesh Kumar Sharma 1/20/2014 24
  25. 25. VALIDATION OPTIONS In the WHO text and EEC guide four options have been recommended namely, Prospective validation Concurrent validation Retrospective validation Revalidation Rakesh Kumar Sharma 1/20/2014 25
  26. 26. The process validation, normally, should be completed prior to distribution and sale of finished dosage forms. Such a validation is called prospective validation. When the process is validated during routine production of formulation. Such a validation is called concurrent validation. When the processes are well established and a number of batches have been produced, such process may be validated Retrospectively. Rakesh Kumar Sharma 1/20/2014 26
  27. 27. Prospective Process validation Prospective process validation should be carried out only when the following operations and procedures have been completed satisfactorily:It should be ensured that facilities and equipment meet GMP’s requirements. Rakesh Kumar Sharma 1/20/2014 27
  28. 28. The persons who will run the validation batches should have understanding of the process and its requirements. Critical processing steps and process variables should be identify using pilot laboratory batches. Detailed technical information on the product and the manufacturing process should be obtained. Rakesh Kumar Sharma 1/20/2014 28
  29. 29. At least one qualification trial using pilot production batch should be made to show that there were no significant deviations from the expected performance of the process. Usually two or three pilot production batches are prepared for validation. While preparing these batches following points may be considered. Rakesh Kumar Sharma 1/20/2014 29
  30. 30. Different lots of raw materials should be used. Batches should be run in succession on different days. Batches should be manufactured in the equipment and other facilities meant for commercial production. Critical process variables should be set within their upper and lower control limits during process operation. Rakesh Kumar Sharma 1/20/2014 30
  31. 31. Retrospective Validation This option of validation is chosen for established products and where prospective validation cannot be justified for economic considerations and resource limitations. Following method can be used for retrospective validation Collect numerical values of in process data and end – product testing result. Organize these data in chronological order using spread sheet formula. Rakesh Kumar Sharma 1/20/2014 31
  32. 32. Include data from at least 20-30 batches for analysis Reduce the number of data to be included in analysis by eliminating test results from non-critical processing steps Subject the data to analysis and evaluation. Draw conclusions as to the state of control of the manufacturing process. Issue a report of the findings Rakesh Kumar Sharma 1/20/2014 32
  33. 33. Usually one or more of the following measured responses are selected for statistical analysis. For solid dosage forms Assay result from uniformity test Tablet hardness value Tablet thickness value Tablet/ capsule weight variation Tablet/ capsule dissolution time Tablet/ capsule disintegration time Rakesh Kumar Sharma 1/20/2014 33
  34. 34. Concurrent validation In-process monitoring of critical processing steps can show that manufacturing process is in state of control. Such a validation is called concurrent validation. In-process tests that can be monitored in solid dosage forms are: Powder-blend uniformity Moisture content Granule size distribution Content uniformity Weight variation Disintegration/ dissolution time Hardness Selection of in-process test parameters should be made on the basis of the critical processing variables to be evaluated. Rakesh Kumar Sharma 1/20/2014 34
  35. 35. For semisolids and liquid dosage forms pH values viscosity density color unit weight variation average particle size potency value Rakesh Kumar Sharma 1/20/2014 35
  36. 36. Revalidation: US FDA guidelines on general principles of Process revalidation is recommended whenever there are changes in critical component like packaging, formulation change in the facility, equipment, critical part of the equipment increase or decrease in batch size Batch fail to conform product specifications for example batch fail in uniformity test, dissolution test etc. Rakesh Kumar Sharma 1/20/2014 36
  37. 37. VALIDATION OF WET GRANULATION PROCESS Wet granulation parameters to be considered during development and validation are Binder concentration and addition: The optimal binder concentration will need to be determined for the formulation. If the binder is to be sprayed, the binder solution needs to be diluted enough so that it can be pumped through the nozzle. It should also be sufficiently concentrated to form granules without overwetting the materials. Rakesh Kumar Sharma 1/20/2014 37
  38. 38. Amount of binder solution: how much binder or solvent solution is required to granulate the materials?. Too much binder or solvent solution will over wet the materials and prolong the drying time. Rakesh Kumar Sharma 1/20/2014 38
  39. 39. Binder solution addition rate: Define the rate at which the binder solution can be added to the material. Mixing time: How long the material should be mixed to ensure proper formation of granules. Over mixing the granulation can lead to harder granules and a lower dissolution rate. Granulation end point: How is the granulation end point determined? Is it controlled by specifying critical processing parameters?. Rakesh Kumar Sharma 1/20/2014 39
  40. 40. Does the wet granulation need to be milled to break up the lumps and enhance drying of the granulation?. Wet granules that have a wide aggregate range can lead to inefficient drying. Factors to consider are: Equipment size and capacity: the mill should be large enough to delump the entire batch within a reasonable time period to minimize manufacturing time and prevent the material from drying during this operation. Rakesh Kumar Sharma 1/20/2014 40
  41. 41. screen size: The screen needs to be small enough to delump the material, but not too small to cause excessive heating of the mill, resulting in drying of the granulation. Mill speed: The speed should be sufficient to efficiency delump the material without straining the equipment Feed rate: the feed rate of the wet granulation is interrelated to screen size and mill size and speed. Rakesh Kumar Sharma 1/20/2014 41
  42. 42. Tablet compression Compression is a critical step in the production of tablet dosage forms. The material being compressed will need to have adequate flow and compression properties. Factors to consider during compression are as follows Tooling: The shape, size and concavity of the tooling should be examined. Rakesh Kumar Sharma 1/20/2014 42
  43. 43. Compression speed and force: compression speed of the tablet press is adjusted based on the flow rate of the granulation, tablet weight required and tablet hardness required. The following in-process tests should be carried out during the compression stage Appearance, Hardness, tablet weight, friability, disintegration, weight uniformity. Rakesh Kumar Sharma 1/20/2014 43
  44. 44. TABLET COATING Key area to consider for film coating of tablets Tablet properties: tablet properties such as hardness, shape are important to obtain good film coated tablets. Equipment type: the type of coater will need to be selected. Conventional or perforated pan and fluid bed coaters are potential options. Rakesh Kumar Sharma 1/20/2014 44
  45. 45. Coater load: what is the acceptable tablet load range of the equipment? Having too large a pan load could cause attrition of the tablets. In case of fluid bed coater, there may not be sufficient airflow to fluidized the tablets. Rakesh Kumar Sharma 1/20/2014 45
  46. 46. Pan speed: what is optimum pan speed?. This will be interrelated to other coating parameters, such as inlet temp, spray rate. Spray guns: the number and types of guns should be determined in order to efficiently coat the tablets. The location and angle of the spray gun(s) should be positioned to get adequate coverage. Having the guns positioned too close together can lead to the tablets to be overwet. Rakesh Kumar Sharma 1/20/2014 46
  47. 47. Spray rate: the optimal spray rate should be determined. Spraying too fast will cause the tablets to become overwet, resulting in clumping of the tablets. Spraying too slowly will cause the coating materials to dry before adhesion to the tablets. This will result in rough tablet surface. Rakesh Kumar Sharma 1/20/2014 47
  48. 48. Inlet/outlet temperature: These parameters are interrelated and should be set to ensure that the atomized coating solution reaches the tablet surface and then is quickly dried. Coating solution: The concentration and viscosity of the coating solution will need to be determined. The solution will need to be sufficiently diluted in order to spray the material on the tablets. Rakesh Kumar Sharma 1/20/2014 48
  49. 49. Coating weight: a minimum and maximum coating weight should be established for the tablet. Sufficient coating material should be applied to the tablets to provide a uniform appearance. Rakesh Kumar Sharma 1/20/2014 49
  50. 50. Residual solvent level: if the organic solvent used for tablet coating, the residual solvent level will need to be determined. In-process testing includes Appearance, cracking or peeling of the coating Color uniformity Disintegration time Tablet hardness. Rakesh Kumar Sharma 1/20/2014 50
  51. 51. EQUIPMENT EVALUATION In an ideal situation, the equipment used to manufacture tablet dosage forms would be selected based on such factors as formulation, safety requirements, handling/production efficiencies, and commercial demands. Rakesh Kumar Sharma 1/20/2014 51
  52. 52. MIXER/GRANULATOR a. What is the method of mixing (e.g., planetary, pneumatic)? b. Is the equipment capable of providing low and/or high shear to the material? c. Can the mixing be varied (e.g., changing the rpm of the impeller)? d. Does the mixer/granulator have a monitoring system (e.g., end point detection) or can it accommodate one? Rakesh Kumar Sharma 1/20/2014 52
  53. 53. e. What is the working load range and capacity of the equipment? f. How is material charged and discharged from the unit? Is it manual, semi-automated, or automated? g. Are there options to introduce the granulating fluid (e.g., dump, meter, or spray)? Rakesh Kumar Sharma 1/20/2014 53
  54. 54. DRYER a. What is the operating principle of the dryer (e.g., direct heating—fluid bed, indirect conduction—tray, or indirect radiant—microwave)? b. Will the wet material be static (e.g., tray) or fluid (e.g., fluid bed)? c. What is the working load range and capacity of the equipment? d. What is the heating range and airflow capabilities of the equipment? Rakesh Kumar Sharma 1/20/2014 54
  55. 55. e. What is the heat distribution of the unit? Are there any hot and/ or cold spots? f. Can the unit pull a vacuum? What is the vacuum range of the unit? g. Can the equipment handle different types of filter bags? For example, can a filter bag be dedicated to a particular product? Rakesh Kumar Sharma 1/20/2014 55
  56. 56. TABLET COMPRESSION MACHINE a. How many compression stations does the compressor have? b. What is the operating range (rpm) of the unit? c. What is the output range of the compressor (e.g., tablets per min)? Will the unit meet the demands (sales forecast) for the product? d. What kind of powder feeding capabilities does the equipment have (e.g., gravity, power-assisted, or centrifugal)? Can this capability be altered or controlled (e.g., open feed frame, forced below feeder)? Rakesh Kumar Sharma 1/20/2014 56
  57. 57. e. What is the compression force range of the equipment? f. Is the equipment capable of monitoring compression and ejection force? g. Does the unit have precompression capabilities? h. How long can the equipment operate without routine maintenance? Rakesh Kumar Sharma 1/20/2014 57
  58. 58. TABLET COATER a. What is the coater type (e.g., pan or fluid bed)? b. Is the pan perforated? c. Can the coater accommodate different size pans? d. What is the working capacity range of the coater (i.e., pan load)? e. Does the pan coater have a ―variable drive‖ capability? This maybe needed to achieve proper tablet mixing in the pan so that the coating solution is applied uniformly to the tablets. Rakesh Kumar Sharma 1/20/2014 58
  59. 59. f. Can the angle of the pan’s pitch be varied? g. What kind of air input (volume and temperature) and vacuum drag-off is required for optimal operation of the coater? These utility requirements may exceed the capacities available in the plant. Rakesh Kumar Sharma 1/20/2014 59
  60. 60. h. What type of spray system can be used with the equipment? i. What is the shape of the coating pan (e.g., oval, mushroom, round)? The shape characteristic will affect the degree of agitation and the direction of tablet flow in the pan. The spray nozzle configuration will have to be designed to ensure adequate spray coverage over the tablet bed. Rakesh Kumar Sharma 1/20/2014 60
  61. 61. j. Is it possible to utilize the equipment for sugar coating as well as film coating? Certainly, if this were possible, capital expenditures would be reduced. k. Is it possible to modify the pan with the installation of baffles? Baffles may be needed to ensure good tablet movement in the pan. l. Can various solvents (ethanol) be used in the equipment? Rakesh Kumar Sharma 1/20/2014 61
  62. 62. THANKS Rakesh Kumar Sharma 1/20/2014 62