World Health Organization

World Health Organization
19 April, 2017 Supplementary Training Modules on Good Manufacturing Practice Validation In this supplementary training module, we will be looking at the recommendations by WHO, on Validation and qualification. The module consists of 7 parts: Part 1. General overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation Part 4. Analytical method validation Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation Each part deals with a specific topic, and each part can be presented in about one to one and a half hours time. Presenters should know the topics and add practical examples to the texts taken from the WHO guideline. WHO Technical Report Series, No. 937, Annex 4.

19 April, 2017 Validation Part 1. General overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation Part 4. Analytical method validation Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation

19 April, 2017 Supplementary Training Modules on Good Manufacturing Practice Non sterile product process validation Part 7 WHO Technical Report Series, No. 937, Annex 4. Appendix 7.

Validation World Health Organization 19 April, 2017 Objectives To discuss non-sterile process validation, focusing on: General recommendations Prospective validation Concurrent validation Retrospective validation Revalidation Change control Objectives To discuss Non-sterile process validation, focusing on: General recommendations Prospective validation Concurrent validation Retrospective validation Revalidation Change control

Validation 19 April, 2017 Principle Documented evidence: Process is capable of reliably and repeatedly rendering a product of the required quality Planning, organizing and performing process validation Process validation protocols Data collected and reviewed against predetermined acceptance criteria – recorded in validation report Principle Documented evidence: Process is capable of reliably and repeatedly rendering a product of the required quality. Planning, organizing and performing process validation Process validation protocols Data collected and reviewed against predetermined acceptance criteria – recorded in validation reports. 1.1 – 1.2

Validation 19 April, 2017 Scope General aspects of process validation for the manufacture of non-sterile finished products Should cover at least the critical steps and parameters, i.e. those that may have an impact on the quality of the product 2. Scope 2.1 These guidelines describe the general aspects of process validation for the manufacture of non-sterile fi nished products. 2.2 Normally process validation should cover at least the critical steps and parameters (e.g. those that may have an impact on the quality of the product) in the process of manufacturing a pharmaceutical product.S 2.1 – 2.2

Validation 19 April, 2017 General Policy and approach to be documented e.g. in a validation master plan – including critical process steps and parameters Process validation to start after qualification of support systems and equipment is completed In some cases - concurrently with PQ Normally completed prior to the manufacture of finished product that is intended for sale (prospective validation) During routine production (concurrent validation) General 3.1 The policy and approach to process validation should be documented, e.g. in a validation master plan, and should include the critical process steps and parameters. 3.2 Process validation should normally begin only once qualification of support systems and equipment is completed. In some cases process validation may be conducted concurrently with performance qualification. 3.3 Process validation should normally be completed prior to the manufacture of finished product that is intended for sale (prospective validation). Process validation during routine production may also be acceptable (concurrent validation). 3.1 – 3.3

Validation 19 April, 2017 Prospective validation Critical factors or parameters possibly affecting finished product quality to be identified during product development Breakdown of production process into individual steps Evaluate each step Determine the criticality of these factors through a “worst-case” challenge where possible 4. Prospective validation 4.1 Critical factors or parameters that may affect the quality of the finished product should be identified during product development. To achieve this, the production process should be broken down into individual steps, and each step should be evaluated (e.g. on the basis of experience or theoretical considerations). 4.2 The criticality of these factors should be determined through a “worst-case” challenge where possible. 4.1 – 4.2

Validation 19 April, 2017 (continued) Prospective validation protocol should include: description of the process and of the experiment equipment and/or facilities to be used including measuring or recording equipment (and its calibration status) variables to be monitored details of the samples to be taken product performance characteristics/attributes to be monitored, together with the test methods acceptable limits and time schedules personnel responsibilities details of methods for recording and evaluating results, including statistical analysis 4.3 Prospective validation should be done in accordance with a validation protocol. The protocol should include: — a description of the process; — a description of the experiment; — details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status; — the variables to be monitored; — the samples to be taken — where, when, how, how many and how much (sample size); — the product performance characteristics/attributes to be monitored, together with the test methods; — the acceptable limits; — time schedules; — personnel responsibilities; and — details of methods for recording and evaluating results, including statistical analysis. 4.3

Validation 19 April, 2017 Approach: Equipment, production environment and analytical testing methods – already fully validated e.g. during installation qualification and operational qualification Appropriately trained personnel and batch manufacturing documentation prepared after these critical parameters have been identified, and machine settings, component specifications and environmental conditions have been determined and specified 4.4 All equipment, the production environment and analytical testing methods to be used should have been fully validated (e.g. during installation qualification and operational qualification). 4.5 Personnel participating in the validation work should have been appropriately trained. 4.6 Batch manufacturing documentation to be used should be prepared after these critical parameters of the process have been identified, and machine settings, component specifications and environmental conditions have been determined and specified. 4.7 A number of batches of the final product should then be produced. The number of batches produced in this validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation.S 4.4 – 4.6

Validation 19 April, 2017 Approach (2) A number of batches of the final product should then be produced What number of batches? sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation Data within the finally agreed parameters from at least three consecutive batches, giving product of the desired quality may be considered acceptable 4.7 A number of batches of the final product should then be produced. The number of batches produced in this validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation.S 4.7 – 4.8

Validation 19 April, 2017 Approach (3) Same size batches Full-scale production batch size If not possible – reduced batch size considered Validity of assumptions made should be demonstrated when full-scale production starts Extensive testing at various stages in the manufacturing process – including on the final product and its package 4.9 The batches should be of the same size, and should be the same as the batch size intended in full-scale production. Where this is not possible, the reduced batch size should be considered in the design of the protocol and when full-scale production starts, the validity of any assumptions made should be demonstrated. 4.10 Extensive testing should be performed on the product at various stages during the manufacturing process of the batches, including on the final product and its package. 4.9 – 4.10

Validation World Health Organization 19 April, 2017 Setting Limits: may include Marketing authorization limits stability specifications Release specification Validation limits 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. Marketing authorization limits based on stability specifications Batch release limits Validation limits

19 April, 2017 Validation Determining critical control point: example of a tablet granulation process Particle size distribution of the active(s) Blending time for the powder Granulating time and speed; amount of granulating fluid and binder concentration Drying time – final moisture content, granule particle size distribution Granule active content and homogeneity, blending time of external phase 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.

Validation 19 April, 2017 Determining critical control points 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.)

Validation World Health Organization 19 April, 2017 Solid dose mixing (1) Homogeneity in blending – the key to quality! Sampling strategy Sample site, label, container Storage Transport Sample thief 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.

19 April, 2017 Validation Solid dose mixing (2) In situ analysis Methods of analysis Statistical analysis inter-batch intra-batch within-sample-site 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.

Validation World Health Organization 19 April, 2017 Tablet compression variables Fill volume Pre- and compression force Turntable speed Dwell time Granule size and feed Ejection force, lubrication 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.

Validation World Health Organization 19 April, 2017 Tablet compression parameters Mass Hardness Moisture Friability Disintegration Dissolution Thickness 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

Validation World Health Organization 19 April, 2017 Tablet coating variables Spray rate Inlet and outlet air temp Coating weight 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

Validation 19 April, 2017 Results in the report that includes, e.g. process description including details of critical steps detailed summary of the results obtained from in-process and final testing, including data from failed tests raw data or reference to these any work done in addition to that specified in the protocol any deviations from the protocol with an explanation a review and comparison of the results with those expected formal acceptance or rejection of the work by the team or persons designated as being responsible for the validation, after completion of any corrective action or repeated work 4.11 The results should be documented in the validation report. As a minimum, the report should include: • a description of the process: batch/packaging document, including details of critical steps; • a detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included, reference should be made to the sources used and where it can be found; • any work done in addition to that specified in the protocol, or any deviations from the protocol should be formally noted along with an explanation; • a review and comparison of the results with those expected; and • formal acceptance or rejection of the work by the team or persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 4.11

Validation 19 April, 2017 Conclusion and recommendation: Made on the basis of the results obtained Incorporated into the batch manufacturing and batch packaging documents and/or standard operating procedures (SOPs) for routine use Limits and frequencies of testing and monitoring should be specified. Actions in case of OOL If validation batches are to be sold or supplied: manufactured under GMP conditions Compliance with the marketing authorization 4.12 A conclusion and recommendation should be made on the extent of monitoring and the in-process controls necessary for routine production, on the basis of the results obtained. 4.13 The conclusion and recommendation should be incorporated into the batch manufacturing and batch packaging documents and/or standard operating procedures (SOPs) for routine use. Limits and frequencies of testing and monitoring should be specified. Actions to be taken in the event of the limits being exceeded should be specified. 4.14 Batches manufactured as part of the validation exercise, and intended to be sold or supplied, should have been manufactured under conditions that comply fully with the requirements of good manufacturing practice and the marketing authorization (where applicable). 4.12. – 4.14.

Validation 19 April, 2017 Concurrent validation May be appropriate to validate a process during routine production Can you give any examples? Decision made by appropriately authorized personnel Premises and equipment previously qualified Done as per validation protocol; and results documented in the validation report Concurrent validation 5.1 In certain cases, it may be appropriate to validate a process during routine production, e.g. where the product is a different strength of a previously validated product, a different tablet shape or where the process is well understood. 5.2 The decision to carry out concurrent validation should be made by appropriately authorized personnel. 5.3 It is essential that the premises and equipment to be used during concurrent validation have been previously qualified. 5.4 Prospective validation should be done in accordance with a validation protocol. 5.5 The results should be documented in the validation report. 5.1 – 5.5

Validation 19 April, 2017 Retrospective validation Comprehensive review of historical data Requires a protocol and a report with a conclusion and a recommendation Not the preferred method of validation, and used in exceptional cases only: e.g. for well-established processes Inappropriate in case of changes (e.g. equipment) Retrospective validation 6.1 Retrospective validation is based on a comprehensive review of historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. This type of validation also requires the preparation of a protocol, the reporting of the results of the data review, a conclusion and a recommendation. 6.2 Retrospective validation is not the preferred method of validation and should be used in exceptional cases only. It is acceptable only for well-established processes and will be inappropriate where there have been changes in the composition of the product, operating procedures or equipment. 6.1 – 6.2

Validation 19 April, 2017 Retrospective validation (2) Sufficient data to be reviewed to provide a statistically significant conclusion Satisfactory results of retrospective validation only serve as an indication that the process does not need to be subjected to validation in the immediate future 6.3 Sufficient data should be reviewed to provide a statistically significant conclusion. 6.4 When the results of retrospective validation are considered satisfactory, this should serve only as an indication that the process does not need to be subjected to validation in the immediate future. 6.3 – 6.4

Validation 19 April, 2017 Revalidation Standard processes (with conventional equipment) data review similar to retrospective validation Points to be considered: the occurrence of any changes in the master formula, methods, starting material manufacturer, equipment and/or instruments calibrations and preventive maintenance carried out standard operating procedures (SOPs) cleaning and hygiene programme 7. Revalidation Note: see main text on “Validation”. The need for periodic revalidation of non-sterile processes is considered to be a lower priority than for sterile processes. 7.1 In the case of standard processes using conventional equipment, a data review similar to that which would be required for retrospective validation may provide an adequate assurance that the process continues to be under control. The following points should also be considered: — the occurrence of any changes in the master formula, methods, starting material manufacturer, equipment and/or instruments; — equipment calibrations and preventive maintenance carried out; — standard operating procedures (SOPs); and — cleaning and hygiene programme. 7.1

Validation 19 April, 2017 Change control In case of changes, consider the change and its impact on the process validation Examples of changes (requiring revalidation): manufacturing process (e.g. mixing times, drying temperatures) equipment (e.g. addition of automatic detection systems) production area and support system changes transfer of processes to another site unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data) Change control 8.1 Products manufactured by processes that have been subjected to changes should not be released for sale without full awareness and consideration of the change and its impact on the process validation. 8.2 Changes that are likely to require revalidation may include: — changes in the manufacturing process (e.g. mixing times, drying temperatures); — changes in the equipment (e.g. addition of automatic detection systems); — production area and support system changes (e.g. rearrangement of areas or a new water treatment method); — transfer of processes to another site; and — unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data). 8.1 – 8.2

Validation 19 April, 2017 Suspensions Syrups Non sterile products Capsules Creams Ointments Tablets

Validation 19 April, 2017 Non sterile products List some of the key parameters to be considered in the process validation of the dosage forms mentioned 2.4

Validation 19 April, 2017 Prospective validation SUMMARY Ask te participants about principle elements of the topic on the slide

Validation World Health Organization 19 April, 2017 Prospective validation SUMMARY Concurrent validation Ask te participants about principle elements of the topic on the slide

Validation World Health Organization 19 April, 2017 Prospective validation SUMMARY Concurrent validation Retrospective validation Ask te participants about principle elements of the topic on the slide

Validation 19 April, 2017 Prospective validation SUMMARY Concurrent validation Revalidation Retrospective validation Ask te participants about principle elements of the topic on the slide

Validation 19 April, 2017 Prospective validation SUMMARY Concurrent validation Revalidation Retrospective validation Ask te participants about principle elements of the topic on the slide Change control

Validation World Health Organization 19 April, 2017 Group Session You are given a tablet manufacturing flow chart to study List the critical steps that are required to be validated List the critical equipment required to be qualified Identify the variables and construct a table as directed In this group session, (see handout ) 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.

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