Validation03

Editor's Notes

• #2: Part 3 of Module 1 on Process validation. The suggested time for Part 3 is 45-60 minutes. At the conclusion of this part there is an optional group session (60 minutes). (Note for the trainer: the times noted are very approximate.)
• #3: The objectives of Part 3, Module 1 will review the following: Validation, risk analysis, and critical steps of processing: The participants will be introduced to risk analysis as a means of identifying critical steps of manufacture and critical products. Solid dose and sterile product process validation: Specific requirements for some pharmaceutical forms will be reviewed. Validation of other pharmaceutical dosage forms is not covered in this module. Finalization of validation will be reviewed, including the preparation of the final report
• #4: <number> This section deals with the subject of validation of pharmaceutical processes, which is a requirement of the WHO guidelines on Good Manufacturing Practices for Pharmaceuticals. Process validation is important to ensure that the drug product can repeatably and reliably meet its predetermined specifications for the strength, quality, purity and stability. Pharmaceutical validation includes analytical method validation (which will be covered in Part 4) and manufacturing or process validation. For a validated manufacturing process, the current good manufacturing practice requires that a well-written procedure for process controls be established to monitor the performance of the manufacturing process. Assurance of product quality is derived from careful attention to a number of factors including selection of quality starting materials, adequate product and process design, control of the process, and in-process and end-product testing. Routine end-product testing alone usually is not sufficient to assure product quality for several reasons, namely: some end-product tests have limited sensitivity. In some cases, destructive testing may be required to show that the manufacturing process is adequate, and in other situations end-product testing will not reveal all the variations that may occur in the product that may impact on safety and effectiveness. The solution to these problems is process validation.
• #5: Reliable, repeatable, under control: The manufacturer must demonstrate that the process is reliable, repeatable, and under control by validating, typically, at least the first three consecutive production batches. There must be no failed batch without a “failure investigation” with root cause analysis and corrective action. If there is a change to the experimental method required, the rationale must be documented. All deviations, decisions and reasoning must be documented. Validation does not improve processes. It can only confirm or deny that the process has been properly developed and is under control. Bad processes should not be validated; for example, containers cannot be sterilized by immersion in isopropyl alcohol. Similarly, validation of badly formulated products should not be attempted.
• #6: We were briefly introduced to DQ, IQ , OQ and PQ in Module 4 of the WHO Basic Training series. Validation starts in development and continues until the stage of full-scale production. In the course of development, critical processes, steps or unit operations are identified. The GMP Inspector should determine that the manufacturer has appropriately identified the following: Check that the premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP. This normally constitutes Design Qualification or DQ. Check that the premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification or IQ. Check that the premises, supporting utilities and the equipment operate in accordance with their design specifications. This constitutes Operational Qualification or OQ. Performance qualification and process validation: Check performance qualification protocols and reports and that process validation has been done. Validation will ensure that a product will meet its predetermined specifications and quality attributes. The whole process then cycles in a review and change phase, since each process has a finite life cycle: Design – user or process requirementsInstall - installation qualificationOperate - operational qualificationValidate - process qualification and process validation Review - periodically - change control
• #7: Critical factors or parameters: Need to be determined Need to be monitored during validation May affect the quality of the product
• #8: Setting limits: Marketing authorization limits: usually the national compendia limits or those agreed at the time of product registration. The product must meet these at any time that it is on the market and within its expiry date. Stability specifications: The specification minimally needed to maintain required potency over the shelf life of the product, based on stability study data. Release specification: the product must meet at the time of release and in order to allow for any changes (super-potency, sub-potency, dissolution, disintegration, etc) over shelf life of product. This is the simplest criteria for setting validation acceptance testing, but will not necessarily include process capability. In the development of acceptance criteria, all three of the above specification areas must be taken into consideration, including an analysis of data gathered during the initial development and stability work. In most cases, this data will be limited but will give enough information on test and process variability to allow for some guidance. The most important thing to remember is to keep the statistics simple. Validation acceptance criteria may be tighter than, or equal to the release limits, which may be tighter than, or equal to the compendial limits.
• #9: Determination of critical control points is a way of ensuring validation effort is not wasted and to identify quality control points. For tablets manufactured by granulation and compression, the critical mixing parameters may include: particle size distribution of the active pharmaceutical ingredient(s) blending time for the powder granulating time and speed amount of granulating fluid-binder concentration drying time - final moisture content, granule particle size distribution granule active content and homogeneity, blending time of external phase In the production of higher risk prescription tablets, especially those containing low dose of active(s), compressed tablet uniformity should be checked more intensively than uniformity of bulk blend study. The next slide shows how to “flow chart” a process to determine critical control points.
• #10: A useful strategy to determine which steps to study intensively, is to “flow chart” the process and conduct a hazard analysis of critical control points. Critical control points indicate critical processing steps. It is necessary to note how often critical control points come at the end stages as the value-adding process proceeds. The flow chart above shows a tablet granulation process where Step XVI and XVIII have been identified as a critical control point. Blend uniformity and cleaning validation has to be performed at step XVI, and during actual manufacture, a reconciliation of the actual yield against the expected yield must be performed before the tablet compression step. (The trainer should explain that this diagram is incomplete, as there are other IQ, OQ, PQ requirements, steps, etc. to be included The slide provides an example only.)
• #11: Solid dose mixing: Homogeneity in blending - the key to quality In pharmaceutical production, the blending step (whether for solid - or liquid - dose forms) is one of the most critical in the process. Type of blender, load, time and speed are the most critical parameters. Additionally, the density, particle size and moisture or solvent content of the powders all affect the time to achieve a homogeneous blend. Minor changes (within specification), are present in the starting materials for any mixture. Sampling strategy: the number of samples to be drawn and the sample sites must be specified. Samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the tablet or capsule “content uniformity” test. The samples to be properly labeled with date, time, location, batch details, sampler. Sample container needs to be appropriate: air tight, inert, etc. The samples need to be carefully handled, stored, and transported to the laboratory to avoid de-mixing or fracturing the granulate. Analysis should commence promptly to avoid sample deterioration. Sampling probe: samples of the mixture are withdrawn by a “thief”, which takes samples from several depths throughout the blender. The volume taken must be in proportion to the mass of the unit dose. This method of grabbing a sample, extracting and performing a wet chemical analysis is potentially inaccurate and is certainly time-consuming.
• #12: Solid dose mixing: (Contd) There are now manyin situ spectroscopic approaches, such as infrared (IR), near-infrared (NIR), and Raman spectroscopy, which are fast, accurate and easily performed. Probes may be placed directly into the mixing vessel or be positioned at windows along the walls of the vessels, allowing for real-time, uninterrupted homogeneity measurements. Remember uniformity or homogeneity are being considered, not a determination of the active. Although the best marker is the active (must be the active for low dose and potent product), the marker can be chosen if it is representative of the blend. The methods of analysis for these samples of the blend are extracted and assayed by UV or HPLC, or similar validated test method. Note that non-specific methods are satisfactory – which is a big difference from e.g. stability studies. The actual spectra (from, for example, near-Infrared) and methods of calculating the homogeneity of the actives should be subject to statistical analysis. The within-sample-site variability must also be acceptable for low dilution powders, such as micro-dose tablets or capsules. This can usually be demonstrated on just the first batch, not for each of the three batches. It is a “minivalidation” of the sampling thief and sampling method used.
• #13: The tablet compression variables include: Fill volume: tableting and capsulation use a volumetric fill. A tableting press equipped with a pressure-transducer will help in collecting statistical data on the uniformity of die-fill and, therefore, on mass uniformity. Pre-compression force; compression force Turntable speed Dwell time Granule feed and uniformity. Granules made by the wet granulation method are less prone to de-mixing than dry granulation. This is critically important for microdose tablets (or capsules). Ejection force - lubrication (e.g. magnesium stearate) During validation studies, the testing of the solid dose form to a greater extent than the normal routine quality control is required, e.g. several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then treated statistically to verify normal distribution and standard deviation. Confidence limits for individual results and for batch homogeneity are also estimated.
• #14: The critical tablet parameters may include: Tablet mass Tablet hardness Moisture Friability Disintegration Dissolution Thickness - if it affects packaging performance If the tablet is film coated, the following additional parameters may require validation: Spray rate of coating solution Inlet and outlet air temperatures Coating weight with respect to tablet appearance, friability, disintegration, and dissolution
• #15: Sterilization by moist heat is conducted under pressure, in the absence of air (which can act as an insulator) in an autoclave. More sophisticated equipment may use heated water spray or a “ballasted” mixture, but the following principles still apply. Moist heat lethality depends on many factors in combination: Time, temperature, pressure Residual air, stability of the product to the process Load: map, porosity, density Bioburden (the number, and resistance profiles of contaminating bacteria) The D value is the time (in minutes) required to reduce a microbiological population by 90%, i.e. one log reduction. The larger the D value, the more resistant the micro-organism is to thermal death. The Z value is the temperature change necessary to produce a 10-fold change in D value. Z = ( T2 - T1 ) (LogD1 - LogD2) F value is a measure of the microbial inactivation capability of a heat sterilization process. Fo is a special value calculated at 121° C with a Z value of 10°C. The Fo is a convenient reference value when comparing different production cycles. One Fo is equal to one minute at 121oC. Fo = 1 x (log10 102 - log10 102) 1 x (2 + 6) = 8 It is expected that there should be not less than Fo8 for effective sterilization.
• #16: Sterilization validation: One of the reasons for the intensity required of sterilization validation is that there are many basic problems with the sterility test (which must still be used to check the validation batches) as follows: Cannot test every type of microbial contamination, ie lack of sensitivity. Subject to an unreasonable rate of error. Repeat testing (if permitted) increases the possibility of passing a contaminated batch. Small number of containers tested with a chance (increasing as the number of tests is repeated) of passing a batch . It will not detect pyrogens or foreign particles. Time, temperature and pressure should be used to monitor the process. The sterilizing conditions in all parts of each type of load to be processed should be demonstrated by physical measurements: calibrated thermocouples, and pressure monitor, position used for controlling and recording should be determined during the validation. Control instrumentation should be independent of monitoring instrumentation and recording charts. Chemical and biological indicators should be used, distributed throughout the load with a focus on the coolest parts determined during OQ studies by thermal mapping. They should not take the place of physical measurements. Loading patterns should be established for all sterilization processes.
• #17: Sterilization validation: (Contd.) Any cooling fluid or gas which may come in contact with the product should be sterilized. Where automated control and monitoring systems are used they should be validated. There should be leak tests on the chamber when a vacuum phase is part of the cycle. Automated control systems or software which controls processes are also required to be validated. Computer validation is not covered by this module. Steam used for sterilization should be of suitable quality (usually Pure Steam of WFI standards) and should not contain contaminating additives. Heat distribution studies should be performed at OQ. Suggested Reading: ISO 11134 Sterilization of health care products - Requirements for validation and routine control of industrial moist heat sterilization ISO 11135 Medical devices - Validation and routine control of ethylene oxide sterilization ISO 11137 Sterilization of health care products -Requirements for validation and routine control - Radiation sterilization ISO/TR 13409 Sterilization of health care products - Dose setting methods for radiation sterilization - Part 1 : Substantiation of 25 kGy for sterilization of small or infrequent production batches ISO/DIS 13408 Aseptic processing of health care products - Part 1 : General requirements
• #18: Dry heat sterilization: Dry heat sterilization has many features in common with moist heat sterilization with respect to IQ, OQ, loading patterns, sterility testing and so forth. The required parameters are: minimum recommended time/temperature cycles: 160° C for not less than 120 min 170° C for not less than 60 min 180° C for not less than 30 min For depyrogenation - 250°C for not less than 30 minutes Air circulation, positive air pressure, HEPA filter: Air should be passed through a HEPA filter. There should be air circulation within the chamber and positive air pressure to prevent the entry of non-sterile air. Advantages: microorganisms are destroyed. depyrogenation is possible; challenge tests using endotoxins should be used as part of the validation. Disadvantages: poor heat transfer higher temperatures, for long time periods.
• #19: Process variation: The process variations are due to many controlled and uncontrolled events. The uncontrolled are due to the natural variation of e.g. machines. One of the outputs of OQ and PQ is the development of attributes for continuous monitoring and maintenance. Process and product data should also be analysed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include: Temperature, Humidity : may be important for tablets, critically important for sterilization Variations in electrical supply: can impact on sterilization processes. Vibration Environmental contaminants Light Human factors (ergonomic factors, stress, etc.). Support with good documentation supervision and training. Variability of materials: starting materials should be subject to a change control procedure after the process is validated. Wear and tear of equipment; revalidation is necessary to check that the equipment is still functioning properly. Appropriate measures should be taken to eliminate controllable causes of variation. Eliminating them will reduce variation and make the process more consistent, resulting in a higher degree of assurance that the product will consistently meet specifications.
• #20: Change control: There must be a review procedure for validated processes. Sometimes this is during an annual product review as equipment is repaired, renewed or replaced; or as new technology emerges. Changes may be necessary to any process as it goes through a life cycle; as new equipment or technology comes into being, or improvements are introduced. Documented change control procedures are needed but “Like for Like" changes do not require re-validation UNLESS they impact on GMP or change the state of validation (IQ, OQ, calibration or PQ). Examples of changes that are likely to require re-validation are given in Part 1 of this module (at slide 21).
• #21: Mixing validation – liquid and solid dose: The mixer type and size must be considered when changes are made. The same technology mixer can be used for pilot studies and then for scale up. Usually one pilot scale study may be permitted as counting towards the three batches requirement. (Note there must still be at least three consecutive batches produced and validated to demonstrate reliability of the process.) The batch size may be increased or decreased as long as it is within the mixer supplier’s specifications and if the batches have been subject to the extremes during validation. Note the scale up must use the same mixing technology; there cannot be a shift from say, a propeller stirrer to a helical stirrer, or from a ribbon mixer to a cube mixer. There may need to be a limit on the proportion of the scale up, say at 10 x the pilot size batch.
• #22: Finalization of the validation process: A validation report must be prepared at the conclusion of validation activities. It should summarize and reference all protocols and results. Obviously, a conclusion is required: “Is the process valid”, but strangely often omitted. The conclusions of the report are sometimes accompanied by a certificate of validity, with an expiry date to ensure revalidation is carried out on time. Good validation practice requires the close collaboration of departments such as those concerned with development, production, engineering, quality assurance and control. This is most important when processes go into routine full-scale production following pharmaceutical development and pilot-plant operations. Consequently, the final report should be reviewed and approved by the validation team. The authorized person, as the overall quality controller, will be a member of the validation team and he or she should have the final decision on whether or not the process is valid and under control.
• #23: <number> In this group session, (see handout 1-3-23) you should list the aspects that you will evaluate when assessing the validation for the project that your group had been given. Identify the critical parameters that should have been evaluated by the manufacturer. List the tests to be carried out and comment on the acceptance criteria to be set.