This document outlines the process of validation for non-sterile pharmaceutical products. It discusses prospective validation, which involves validating the production process prior to releasing finished product for sale, concurrent validation during routine production, and retrospective validation which involves reviewing historical data. The key steps are identifying critical process parameters, conducting validation protocols with predetermined acceptance criteria, and documenting results in a validation report.
1. Supplementary Training Modules on
Good Manufacturing Practice
Validation
WHO Technical Report Series,
No. 937, 2006. Annex 4.
Validation | Slide 1 of 35 August 2006
2. 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
Validation | Slide 2 of 35 August 2006
3. Supplementary Training Modules on
Good Manufacturing Practice
Non sterile product process
validation
Part 7
WHO Technical Report Series, No. 937,
2006. Annex 4. Appendix 7.
Validation | Slide 3 of 35 August 2006
4. Validation
Objectives
To discuss non-sterile process validation, focusing on:
General recommendations
Prospective validation
Concurrent validation
Retrospective validation
Revalidation
Change control
Validation | Slide 4 of 35 August 2006
5. Validation
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
1.1 – 1.2
Validation | Slide 5 of 35 August 2006
6. Validation
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
2.1 – 2.2
Validation | Slide 6 of 35 August 2006
7. Validation
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)
3.1 – 3.3
Validation | Slide 7 of 35 August 2006
8. Validation
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
4.1 – 4.2
Validation | Slide 8 of 35 August 2006
9. Validation
(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
Validation | Slide 9 of 35 August 2006
10. Validation
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 – 4.6
Validation | Slide 10 of 35 August 2006
11. Validation
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 – 4.8
Validation | Slide 11 of 35 August 2006
12. Validation
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 – 4.10
Validation | Slide 12 of 35 August 2006
13. Validation
Setting Limits: may include
– Marketing authorization limits
stability specifications
– Release specification
– Validation limits
Marketing authorization limits
based on stability specifications
Batch release limits
Validation limits
Validation | Slide 13 of 35 August 2006
14. 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
Validation | Slide 14 of 35 August 2006
15. Validation
Determining critical control points
Process step Operation IQ/OQ/PQ requirements
Measure humidity with IQ/OQ
XIII calibration instrument Training
humidity meter
operation, records for
IQ/OQ cleaning, care technician
XIV Weigh granulate - balance and maintenance
calibration
XV Sieve 3/
sieve with sieve type 1
5 I Q/OQ/PQ
XVI Blend Cleaning Critical Cleaning, and Blend
3/5 validation control uniformity required to be
mixer (speed 1, 1 minute)
granulate point established during validation
XVI Blend 2 mixer (speed 1, 30
with 3/5 seconds)
granulate
XVIII Critical Decision as to whether to
Weigh granulate
control compress or not based on
point expected yield and actual yield
Validation | Slide 15 of 35 August 2006
16. Validation
Solid dose mixing (1)
Homogeneity in blending – the key to quality!
Sampling strategy
Sample site, label, container
Storage
Transport
Sample thief
Validation | Slide 16 of 35 August 2006
17. Validation
Solid dose mixing (2)
In situ analysis
Methods of analysis
Statistical analysis
– inter-batch
– intra-batch
– within-sample-site
Validation | Slide 17 of 35 August 2006
18. Validation
Tablet compression variables
Fill volume
Pre- and compression force
Turntable speed
Dwell time
Granule size and feed
Ejection force, lubrication
Validation | Slide 18 of 35 August 2006
19. Validation
Tablet compression
parameters
Mass
Hardness
Moisture
Friability
Disintegration
Dissolution
Thickness
Validation | Slide 19 of 35 August 2006
20. Validation
Tablet coating variables
Spray rate
Inlet and outlet air temp
Coating weight
Validation | Slide 20 of 35 August 2006
21. Validation
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
4.11
– 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
Validation | Slide 21 of 35 August 2006
22. Validation
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. – 4.14.
Validation | Slide 22 of 35 August 2006
23. Validation
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
5.1 – 5.5
Validation | Slide 23 of 35 August 2006
24. Validation
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)
6.1 – 6.2
Validation | Slide 24 of 35 August 2006
25. Validation
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 – 6.4
Validation | Slide 25 of 35 August 2006
26. Validation
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
7.1
Validation | Slide 26 of 35 August 2006
27. Validation
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)
8.1 – 8.2
Validation | Slide 27 of 35 August 2006
28. Validation
Suspensions Syrups
Capsules Non sterile products Creams
Tablets Ointments
Validation | Slide 28 of 35 August 2006
29. Validation
Non sterile products
List some of the key parameters to be considered in the
process validation of the dosage forms mentioned
2.4
Validation | Slide 29 of 35 August 2006
30. Validation
Prospective validation
SUMMARY
Validation | Slide 30 of 35 August 2006
31. Validation
Prospective validation
SUMMARY
Concurrent validation
Validation | Slide 31 of 35 August 2006
32. Validation
Prospective validation
SUMMARY
Concurrent validation
Retrospective validation
Validation | Slide 32 of 35 August 2006
33. Validation
Prospective validation
SUMMARY
Concurrent validation
Revalidation
Retrospective validation
Validation | Slide 33 of 35 August 2006
34. Validation
Prospective validation
SUMMARY
Concurrent validation
Revalidation
Retrospective validation
Change control
Validation | Slide 34 of 35 August 2006
35. Validation
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
Validation | Slide 35 of 35 August 2006
Editor's Notes
दिसंबर 4, 2012 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.
दिसंबर 4, 2012
दिसंबर 4, 2012
दिसंबर 4, 2012 Objectives To discuss Non-sterile process validation, focusing on: General recommendations Prospective validation Concurrent validation Retrospective validation Revalidation Change control
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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
दिसंबर 4, 2012 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 ).
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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
दिसंबर 4, 2012 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
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 Determination of critical control points is a way of ensuring validation effort is not wasted and to identify quality control points. For tablet s 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.
दिसंबर 4, 2012 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.)
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 Solid dose mixing: (Contd) There are now many in 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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: S pray rate of coating solution Inlet and outlet air temperatures Coating weight with respect to tablet appearance, friability, disintegration, and dissolution
दिसंबर 4, 2012 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: S pray rate of coating solution Inlet and outlet air temperatures Coating weight with respect to tablet appearance, friability, disintegration, and dissolution
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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).
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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.
दिसंबर 4, 2012 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).
दिसंबर 4, 2012
दिसंबर 4, 2012
दिसंबर 4, 2012 Ask te participants about principle elements of the topic on the slide
दिसंबर 4, 2012 Ask te participants about principle elements of the topic on the slide
दिसंबर 4, 2012 Ask te participants about principle elements of the topic on the slide
दिसंबर 4, 2012 Ask te participants about principle elements of the topic on the slide
दिसंबर 4, 2012 Ask te participants about principle elements of the topic on the slide
दिसंबर 4, 2012 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.