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Premium member Presentation Transcript : Author: Nageshwar Rao.Mekala Teegala.Krishna Reddy college of Pharmacy, Hyderabad. emai .: email@example.com Saturday, September 14, 2013 1 PROCESS VALIDATION OF SOLID DOSAGE FORMS Process Validation of oral solid dosage forms PowerPoint Presentation: Validation Validation simply means, assessment of validity' or action of proving effectiveness. According to European community for medicinal products, validation is 'action of proving', in accordance with the principles of Good manufacturing practices that any procedures, process, requirement, material, activity or system actually leads to expected results. PowerPoint Presentation: There are several important reasons for validating a product and /or process. Manufacturers are required by law to confirm to GMP regulations. Good business dictates that a manufacture avoid the possibility of rejected or recalled batches. Validation helps to ensure product uniformity, reproducibility, and quality. All pharmaceutical scientists, whether in development, quality assurance, production. IMPORTANCE OF VALIDATION: Regulatory basis for process validation: Regulatory basis for process validation The concept of process validation from its beginning in the early 1970s through regulatory aspects associated with cGMP, applicable to various analytical, quality assurance, pilot plant, production considerations of solid dosage forms. In the early 1990s, the concept of pre approval inspection (PAI) was introduced, in which validation protocols and schedules were introduced. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 4 Process validation : Process validation • According to US Food and Drug Administration, 1987 “ Process Validation” is establishing documented evidence which provides a high degree of assurance that a specified process will consistently produce a product meeting its pre-determined specifications and quality characteristics.” It is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting pre-determined specifications and quality attributes.” Saturday, September 14, 2013 5 Process Validation of oral solid dosage forms Types of process validation: Types of process validation Saturday, September 14, 2013 6 PROCESS VALIDATION RETROSPECTIVE PROCESS VALIDATION PROSPECTIVE PROCESS VALIDATION CONCRURRENT PROCESS VALIDATION Process Validation of oral solid dosage form s DEFINITIONS: DEFINITIONS PROSPECTIVE PROCESS VALIDATION Prospective process validation shall be carried out before the Process is put to commercial use. Minimum 3 consecutive batches to be considered. The important requirement for prospective validation is protocol preparation. RETROSPECTIVE PROCESS VALIDATION “Where historical data taken from the records of the completed production batches are used to provide documented evidence.” CONCURRENT VALIDATION “Established documented evidence that a process is in a state of control during the actual implementation of the process”. Normally performed by conducting in-process testing or monitoring critical operations. Saturday, September 14, 2013 7 Process Validation of oral solid dosage form (Tablet) Process Validation Protocol: Process Validation Protocol 1. General information 2. Objective 3. Background/Pre validation Activities Summary of development and tech transfer (from R&D or another site) activities to justify in-process testing and controls; any previous validations. 4. List of equipment and their qualification status 5. Facilities qualification 6. Process flow chart 7. Manufacturing procedure narrative 8. List of critical processing parameters and critical excipients 9. Sampling, tests and specifications 10. Acceptance criteria Saturday, September 14, 2013 8 Process Validation of oral solid dosage form (Tablet) Validation Process flow chart: Validation Process flow chart Saturday, September 14, 2013 9 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: Validation protocol for manufacturing of tablets Saturday, September 14, 2013 10 Process Validation of oral solid dosage form (Tablet) Validation of raw materials: Validation of raw materials The process validation of solid dosage forms begins with raw materials, both APIs and exceptions. API is most uncontrollable component in the product or process, physical characters like morphology, particle size, surface area, solubility characters may be changed during development of a product. Because these parameters may effect drug activity, solubility, material flow and blend uniformity. Hygroscopic nature of raw materials also important factor. Example: water in soluble drugs are milled or micronized in order to improve dissolution and bioavailability. Particle surface areas are produced during milling micronisation to obtain uniform blend of active ingredient with other excepients. Another important factor is volume of binder or granulating solution required to produce agglomerated mass. Microcrystalline cellulose used as diluents and magnesium stearate used as lubricant. Aluminum lake dye used in direct compression to obtain uniform distribution of color, Dye is added by using geometric addition or pre blend approach is widely used. Saturday, September 14, 2013 Process Validation of oral solid dosage forms 11 Analytical validation : Analytical validation Analytical validation is the evaluation of product quality attributes through testing, to demonstrate reliability is being maintained throughout the product life cycle and that the precision, accuracy, strength, purity and specification has not been compromised. Following criteria must be assessed before beginning of analytical validation: Accuracy of method: The ability of method to measure the true value of sample. Precision of method: The ability of method to estimate reproducibility of any given sample. Specificity: The ability to accurately measure in the presence of another component. In-day/out-day variation: Does the precision and accuracy of the method changes at conducting analytical study and repeated on subsequent days. Between operator variation: Different analysts repeats the precision and accuracy studies using same laboratory and same instruments. Saturday, September 14, 2013 Process Validation of oral solid dosage forms 12 Equipment validation: Equipment validation Validation of equipments is known as qualification. Equipment validation is divided into installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). An IQ documents specific static attributes of a facility or item to prove that the installation of the unit has been correctly performed and that the installation specifications of the manufacturer have been met. OQ After installation it must be ensured that the equipment can deliver operating ranges as specified in the purchase order. This is called OQ. The PQ's are concerned with proving that the process being investigated works as it is supposed to do. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 13 Equipment validation flow chart: Equipment validation flow chart Saturday, September 14, 2013 14 Design or Development of Equipment, System, or Product Installation Qualification Operational Qualification Process Performance Qualification or Process Validation Change Control Process Validation of oral solid dosage form s Some Common Variables In The Manufacture Of Solid dosage forms : Some Common Variables In The Manufacture Of Solid dosage forms Particle size of drug substance Bulk density of drug substance/excipients Powder load in granulator Amount and concentration of binder Mixer speed and mixing times Granulation moisture content Milling conditions Lubricant blending times Tablet hardness Coating solution spray rate Saturday, September 14, 2013 15 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: Industrial Process overview of Solid dosage forms Steps & process parameter are following- (1)Mixing or Blending- Material have similar physical properties will be easier to form a uniform mix or blend as compare to difference in properties. Techniques-1- diffusion(tumble) 2- convection(planetary or high intensity or fluid bed. Mixing or blending depending on various factors- (a)Mixing speed- mixing the drug & excipient will require more intense mixing than adding the lubricant to the final blend. Saturday, September 14, 2013 16 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: ( b)Mixing time- M ixing time will be dependent on the mixing technique & speed. If over mixed occurred at the result de mixing or segregation of the material. ( c)Drug uniformity- Handling of the material are key in obtaining valid content uniformity results . Segregation of the sample can occur by handling resulting inaccurate results. Sample should be equivalent to the weight of a single tablet. ( d)Excipient uniformity- excipient need to be uniform in the granulation. Two keys excipient are- - LUBRICANT- lubricant needs to be distributed uniformly in the mixture/granulation for high speed compression operation . Saturday, September 14, 2013 17 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: Uneven distribution of the lubricant can result in picking & sticking problem during compression. Color- evenly distributed in the mixture so the tablets have a uniform appearance (color, hue & intensity) Uniform dispersed in the blend prior to compression to avoid shading(molting). (e)Equipment capacity/load- T he bulk density of material will affect the capacity of the equipment . Undercharging or overcharging a blender can result in poor drug or tablet lubricant distribution. Saturday, September 14, 2013 18 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: (2)Wet granulation- what type of wet granulation technique will be used? Will it be of- low shear (hobart) - high shear rate (diosna )or fluid bed (glatt) Wet granulation parameters to be processing during development &validation are- (a)Binder addition - should be added as a granulating solution or dry like other excipients. Adding the binder dry avoids the need to determine the optimal binder conc. (b)Binder conc.- if the binder conc. are high they are not ejected by spray nozzle then the binder needs to be dilute enough so that it can be pumped through the spray nozzle. Saturday, September 14, 2013 19 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: (c)Amount of binder solution /granulating solvent- too much binder or solvent solution will over wet the material &prolong the drying time. Amount of binder solution is related to the binder conc. (d)Mixing time— How long materials should be mixed to ensure proper formation of granules. (e)Granulation end point –how is the granulation end point determined? is it determined by granulation end point equipment(eg-ammeter or wattmeter) Saturday, September 14, 2013 20 Process Validation of oral solid dosage form (Tablet) 3)Wet milling: 3)Wet milling wet milling does the wet granulation need to be milled to break up the lumps & enhance drying of the granulation. Wet granules have wide aggregate range and leads to in efficient drying. FACTORS-(a)Equipment size & capacity- mill should be enough large to de lump the entire batch within a reasonable time period to minimize manufacturing time. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 21 PowerPoint Presentation: (b)Screen size screen needs to be small enough to de lump the material but not too small to cause excessive heating of the mill at the result drying of granulation occurred. (c)Mill speed sufficient speed without causing staining the equipment. (d)Feed rate of the wet granulation is interrelated to screen size, mill size & speed Saturday, September 14, 2013 22 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: Type of drying technique (a)tray dryer (b) fluidized bed dryer (c) microwave Changing dryer techniques could affect such tablet properties such as hardness, disintegration ,dissolution & stability . High moisture content can result in- (1)Tablet picking or sticking to tablet punch surfaces 2)Poor chemical properties as a result of hydrolysis . An over dried granulation could result in poor hardness &fraibility. Moisture content are analysed by following method – (1)near I.R (2)loss of drying (3) Karl Fischer FACTORS- (A)Inlet/outlet temp. The inlet temp. is the temperature of the incoming air to dryer ,while the outlet temperature is the temperature leaving the unit. Saturday, September 14, 2013 23 Process Validation of oral solid dosage form (Tablet) 4)Drying PowerPoint Presentation: Inlet temperature should be set high enough to minize drying without affecting the physical/chemical stability. The outlet temperature is an indicator is an of the granulation temperature &will increase toward the inlet temperature as the moisture content of the granulation decreases (vaporization rate). (B)Airflow insufficient air flow could prolong drying &affect the chemical stability. (C)Moisture uniformity moisture content could vary within the granulation Drying is also affect the moisture in the granulation. (D)Equipment capability/capacity: The load that can be efficiently dried within the unit. A larger load requires more moisture to be removed on drying and effect the drying time. Saturday, September 14, 2013 24 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: (5)Lubrication Selection of lubricant what kind of lubricant should be used? Grade of lubricant used Compatibility with other ingredient. ( b)Amount of lubricant how much amount lubricant is required? Too much lubricant will form hyrophobic layer on the tablet resulting dissolution problem. (c)Mixing time how much should the material is mixed to ensure proper formation? Should mixing stop after the addition of the lubricant or should additional mixing be required ? If not mixed long enough from problems like chipping ,capping etc. Saturday, September 14, 2013 25 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: ( 6)Tablet compression : T he material should readily flow from the hopper onto the feed frame & into the dies. Inadequate flow can result in ‘RAT HOLING’in the hopper.this can cause tablet weight &uniformity problem. FACTORS(A) Tooling The size ,shape &concavity of the tooling should be examined based formulation properties &commercial specification. (B)Compression speed range of compression speed to determine the operating range of the compressor. The adequacy of the material’s flow into the dies will be determined by examining the tablet weights. Is a force feeder required to ensure that sufficient material feed into the dies. (C)Compression or ejection force determined optimal compression force to obtain the desired tablet hardness. Saturday, September 14, 2013 26 Process Validation of oral solid dosage form (Tablet) PowerPoint Presentation: The following in-process tests should be examined during the compression stage Appearance Hardness Tablet weight Friability Disintegration Weight uniformity Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 27 PowerPoint Presentation: (7)Tablet coating T ablet coating can occur by different techniques(eg- sugar, film or compression) Key area to consider for tablet coating include the following- (a)Tablet properties – the tablet needs to be enough to withstand the coating process. If tablet attrition occurs ,the tablets will have rough surface appearance Round shape easily coated than multiple sides. Equipment type- coater will need to be selected. Conventional or perforated pan & fluid bed coaters are potential. (c)Coater load - what is the acceptance tablet load range of the equipment? Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 28 PowerPoint Presentation: Too high load at the result attrition occurred. (d)Pan speed- what is the optimal pan speed? It is interrelated to coating parameter such as inlet temperature spray rate & flow rate. (e)Spray guns- number & types of guns should be determined in order to efficiently coat the tablet. Size of spray nozzle properly to ensure even distribution over the tablet bed & to prevent clogging of the nozzles. (f)Spray rate- spray rate should be determined . Spraying too fast will cause the tablets to become over wet, resulting in clumping of the tablets & possible dissolution of the tablet surface. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 29 PowerPoint Presentation: Spray too slowly will cause the coating material to prior to adhesion to the tablets, result in rough & poor coating efficiency. (g)Tablet flow- flow of the tablets in the coater should be examined to ensure proper flow. The addition of baffles may be required adequate movement of the tablet for coating. (h)inlet/outlet temp &air flow - parameter should be set to ensure that the atomized coating solution reaches the tablet surface & then is quickly dried. (i)Coating solution- the conc. & viscosity of the coating solution will need to be determined. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 30 PowerPoint Presentation: In process tests- Moisture content of dried granulation Granulation particle size distribution Blend uniformity Individual tablet/capsule weight Tablet hardness Tablet thickness Disintegration Impurity profile Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 31 PowerPoint Presentation: Moisture content of “dried granulation” : Loss on drying (LOD) used to determine whether or not the granulation solvent has been removed to a sufficient level during the drying operation (usually less than 2% moisture). Granulation particle size distribution: An extremely important parameter that affect tablet compressibility, hardness, thickness, disintegration, dissolution, weight variation, and content uniformity. This parameter done by sieve analysis, should be monitored throughout the tablet validation process. PowerPoint Presentation: Blend uniformity: Samples of the blend are taken and analyzed to ensure that the drug is uniformly dispersed throughout the tablet/capsule blend. The proper blend time must be established so that the blend is not under- or over mixed. Individual tablet/capsule weight: The weight of individual tablets or capsules is determined throughout compression /encapsulation to ensure that the material is flowing properly and the equipment is working consistently. PowerPoint Presentation: The individual weight should be within 5% of the nominal weight. Weight fluctuations or frequent machine adjustments suggest that the formulation (e.g., poor granulation flow) is not optimized and/or that the equipment may need maintenance. Tablet hardness: Tablet hardness is determined periodically throughout the batch to ensure that the tablets are robust enough for coating, packing, and shipping and not too hard to affect dissolution. PowerPoint Presentation: The stability of the coating solution should be investigated to establish its shelf life. (j)Coating weight- a min. & max. coating weight should be established for the tablet (k)Residual solvent level- if solvents are used for tablet coating ,the residual solvent level will need to be determined. APPEARANCE TESTING FOR TABLET COATING- Cracking or peeling of the tablet Intagliation fill-in Color uniformity Coating efficiency should be determined for the coating operation. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 35 PowerPoint Presentation: Finished product tests- Appearance Assay Content uniformity Tablet hardness Tablet friability Impurity profile Dissolution Process validation testing is generally done on the first three batches of product made in production –size equipment. Revalidation testing is only done when a significant change has occurred. Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 36 PowerPoint Presentation: Finished Product Tests 1.Appearance: The tablets should be examined for such problems as tablet mottling, picking of the monogram, tablet filming, and capping of the tablets. If the tablets are colored, the color quality needs to be examined. 2. Content uniformity: Samples are taken across the batch profile (beginning, middle, and end) and analyzed to ensure that the dosage forms comply with compendia standards (±15% of the labeled amount) or more stringent internal limits. It will indicate whether there is de mixing during the manufacturing operation (i.e., segregation during flow of granulation from a storage bin). PowerPoint Presentation: 4. Tablet hardness : A critical parameter for dosage form handling and performance. 5. Tablet friability: Friability is an important characteristic on the tablets’ ability to withstand chipping, cracking, or “dusting” during the packaging operations and shipping. 6. Dissolution: Dissolution is important to ensure proper drug release characteristics (in vitro availability) and batch-to-batch uniformity. 7. Assay: This test will determine whether or not the product contains the labeled amount of drug. PowerPoint Presentation: Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 39 PROCESS VALIDATION OF CAPSULES PowerPoint Presentation: 40 PowerPoint Presentation: 41 Capsule Composition 1. Capsule Shell Provide the reason for the presence of each ingredient in the capsule formula. Justify the level and grade of each ingredient. Explain the selection of the capsule size and shape. Discuss the need for capsule identification (e.g., color or imprinting). 2. Capsule Shell Contents Establish the compatibility of the capsule shell and the capsule contents. Determine the hygroscopic nature of the capsule formulation. For example, a hygroscopic formulation (active ingredient and/or excipients) can pull water from the capsule shell, which could affect the Active ingredient—stability issues such as degradation and morphology changes Formulation—hardening on the materials, resulting in a decreased dissolution rate Capsule shell—more brittle PowerPoint Presentation: 42 B. Process Evaluation and Selection The process to manufacture the contents of a hard gelatin capsule is the same as a tablet. It may required only a blending step, such as a direct compression tablet, or several unit operations, such as a wet granulation tablet (e.g., mixing, wet milling, drying, dry milling, and blending). In either case, the materials are then encapsulated in a capsule shell. C. Encapsulation Encapsulation is a critical step in the production of capsules, similar to the compression step for tablet dosage forms. The materials to be encapsulated will need to have good flow properties and a consistent density. The materials may also need to be compressible in order to be dosed into the capsules ; however,they should also be easily deaggregated so not to adversely affect the dissolutionof the drug. Factors to consider during encapsulation are: PowerPoint Presentation: 43 Encapsulation type : The type of encapsulation technique (e.g., auger, vacuum, dosator) required for the formulation needs to be determined and justified. Examples are Auger: Capsugel Type B or Elanco No. 8 Vacuum: Perry Vibratory: Osaka Dosing disk: H&K Dosator: MG2 or Zanasi The type of technique may be dependent on such factors as drug or formulation properties and equipment availability. Encapsulation speed : The formulation should be encapsulated at a wide range of speeds to determine the operating range of the encapsulator. By examining the capsule weights, the adequacy of the material’s flow will be determined. Types of capsule filling machine: Types of capsule filling machine 44 Conti…: C onti … 45 Conti…: C onti … 46 PowerPoint Presentation: Conclusion Solid dosage form validation should be part of a comprehensive validation program within an industry. The multidisciplinary validation team must identified the product & process characteristics that must be studied & incorporate specific validation tests to ensure that product will meet all quality , manufacturing & regulatory requirements. Continous awareness of validation will produce reproducibility . Saturday, September 14, 2013 Process Validation of oral solid dosage form (Tablet) 47 REFERENCES:: REFERENCES: Nash A.Robert,Wachter H.Alfrad “Pharmaceutical Process Validation” Third Edition,volume 129, Marcel Dekker, Inc, New York, 2003,159-180. http://www.pharmainfo.net/reviews/guidelines-general-principles-validation-solid-liquid-and-sterile-dosage-forms . Berry I.R., and Nash R.A., ”Pharmaceutical Process validation” second edition, revised and expanded; Marcel Dekker series; 83-110 www.usvalidation.com Guideline on General Principles of Process Validation (www.fda.gov/cder/guidance/pv.htm), May 1987) Guideline on General Principles of Process Validation (www.fda.gov/cder/guidance/pv.htm), May 1987) PowerPoint Presentation: The journey of a thousand miles begins with a single step… You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.