module - 4
DESCRIPTION
Module - 4TRANSCRIPT
Introduction to the Training CourseQuality
Basic Principles of GMP
In this section of the programme we are going to address all the issues relating to the quality management of pharmaceutical manufacturing.
Note for the Trainer: these times are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly.
The programme is approximately as follows:
Presentation 30 minutes
Group session I 20 minutes with 20 minutes for feedback
Presentation 30 minutes
Group session II 30 minutes with 30 minutes feed back
Test paper 45 minutes
The timing for the test paper allows 25 minutes for the test itself and the remaining time for a review of the answers.
The timing is flexible since this is a very important area. We want to ensure that the participants really understand this subject.
Module 4 Slide * of 11
Quality
GMP
Diminishes risks that cannot be controlled by testing of product
Cross-contamination
Mix-ups
Good Manufacturing Practice (GMP) is the part of quality assurance that ensures that products are produced and controlled consistently and reliably. This consistency of production and control is essential. It can only come about by having clear descriptions of the way in which the work will be done.
GMP specifically addresses risks that cannot be fully controlled by testing of the final product:
Cross-contamination
Mix-ups
These risks can best be controlled by having a properly managed system of working that takes them into account. This means that there must be good design, sound operation, and planned maintenance of facilities. It also means that the quality checking system must be designed with these risks in mind and set out to find whether any errors have occurred. Let us look at this problem in another way. If we do not know what sort of cross contamination we have, then the work of the analyst is very difficult. The analyst should ideally know what to test for before commencing testing. In other words, if we do not know what the likely cross-contaminant is then we cannot analyse for it.
There are a number of basic requirements for GMP, which we shall look at next.
Module 4 Slide * of 11
Quality
Critical steps validated
Trained operators
Basic requirements for GMP are as follows:
1. Clearly defined and systematically reviewed manufacturing processes. This means that all batch documentation, all quality specifications and all relevant SOPs must be prepared in harmony with one another. It also means that all departments involved must be aware of the work of the other departments in order to eliminate discrepancies. Finally, the quality control staff acting as the overall coordinator of all these activities should be involved in all decisions related to the quality of the production. It is their responsibility to ensure that the activities are aimed at producing products that meet the required specifications. The specifications are approved by the drug regulatory authority.
2. Critical steps of production processes are validated. Since there is variability in the quality of materials and in the performance of the equipment, we need to check whether the process works with all the variability that can arise. This process of checking and documenting variability is known as validation. It means that the company must have sufficient knowledge of its materials, equipment and processes that it knows what variables are likely to arise. It can then carry out controlled experiments to ensure that whatever variables do occur, they can still produce products meeting specifications. Validation is also required if there is a change in any part of the process, materials or equipment used in the manufacturing.
3. Appropriate resources: personnel, buildings, equipment and materials are available to produce a quality product. This means that the company has evaluated all of the elements it needs to produce a product and has sufficient resources of the right quality for its production.
4. Manufacturing is based on clearly written procedures. The procedures referred to here include the batch manufacturing and testing instructions and the SOPs needed for every department. Preparing these procedures and documents is a very important task that needs careful thought. The module on documentation goes into this in more detail.
5. Operators are trained. A company can have "all the documentation in the world" but if its operators are not properly trained to carry out the tasks that they are supposed to perform then the company will not be successful. We will talk more about this in the session on personnel. Operators not only need initial training but also follow-up training.
Module 4 Slide * of 11
Quality
QC / QA is part of GMP
The following QC slides illustrate that quality control is part of good manufacturing practice.
There is a handout to accompany these slides on quality control.
Module 4 Slide * of 11
Quality
Independent from production and other departments is considered to be fundamental
Under the authority of an appropriately qualified and experienced person with one or several control laboratories at his or her disposal.
Each holder of a manufacturing authorization should have a quality control department (except for a holder performing only a fraction of the manufacturing process under a contract).
The independence of quality control from production is considered fundamental. The quality control department should be independent fromother departments and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal.
Module 4 Slide * of 11
Quality
Resources
The quality control department must have adequate resources.
This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
Quality
Responsibilities
Testing
Sampling
Inspecting
Monitoring of all materials and environmental conditions in the factory
Releasing or rejecting materials for production use and finished products
Module 4 Slide * of 11
Quality
Establish QC procedures
Reference standards availability
Stability testing
Complaint investigations
Environmental monitoring
In addition to those already mentioned, the QC department has other duties to carry out, including:
1. Establishing, validating and implementing all QC procedures. All QC procedures need not only to be established in the first instance but also to undergo exactly the same critical review and maintenance process as operating procedures in all other areas.
2. Evaluating, maintaining, storing reference standards. Reference standards are among the most critical materials that QC has to handle. After all, the results of much testing rely upon comparison with an analytical reference standard. If that reference standard has not been looked after properly then all the test results may be incorrect.
3. Ensuring correct labelling of containers of materials and products. We have already mentioned just how critical this activity is. The major difficulty is the problem of seeing that an error has occurred. You are looking at a situation where there are thousands of components often being processed at high speed. It is nearly impossible for operators to see that an error has occurred. Systems must be in operation as the main safeguard. If equipment such as bar code readers are in operation it must be regularly checked for effectiveness.
4. Stability testing of active ingredients and finished products. A stability-testing programme should be developed for all products, described in the form of an SOP. Stability of active pharmaceutical ingredients should be monitored. Active ingredients should be regularly tested within their shelf-life to confirm suitability for continued use. The quality control department should have a very clear role in ensuring that samples are taken for the ongoing stability testing programme and that analysis is undertaken at the right time.
5. Participating in complaint investigations. We will be devoting a whole module to the importance of complaint and recall handling. It is worth repeating that complaints offer an opportunity for the company to learn from mistakes or product design failures. In this way actions can be taken to prevent re-occurrence.
6. Participating in environmental monitoring. There are many sides to environmental monitoring. With regard to products, the environment that we are referring to here is that which can immediately affect product quality. E.g.., swab testing and settle plates in a sterile area, testing of temperature and humidity control. There is another environment that needs to be looked at. External environment checks may be needed.
Module 4 Slide * of 11
Quality
Resources
This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
Quality
Sampling
Records
Failure investigations for all deviations / incidents
Ingredients comply with the marketing authorization
Ingredients are of the required purity / quality
Proper containers
Correct labelling
Any changes to written procedures, systems equipments should be handled
Let’s look at some of these basic requirements for quality control in greater detail:
1. Sampling should be undertaken by methods and personnel approved by the QC department. We described a little earlier the key issues around sampling. It is not a requirement that all sampling needs to be done by quality assurance or quality control personnel. The important point is that it is carried out in such a way that it is representative of the batch and in accordance with an SOP. QC personnel must have access to the production area to undertake sampling when necessary.
2. Validated test methods should be applied. The validation of test methods includes verification of: accuracy, precision, linearity, repeatability, robustness, specificity. This means that the test methods should be challenged to be able to demonstrate that the tests are able to give an accurate result on a repeatable basis. The methods must be capable of being applied with precision. The results obtained must be linear over a range of acceptable responses. Finally, the results must be repeatable over a number of identical tests.
3. Records for sampling, inspecting, testing of materials, intermediates and bulk and finished products need to be kept. It is essential too that the inspector assesses the records of the work done during processing. This means that there will be traceability on what happened.
4. The QC department should review and evaluate the relevant production documentation. This review needs to cover all quality aspects. As part of the documentation procedure, it is important that the quality control department approves all the documentation. This ensures that the manufacturing documentation and the quality assurance documentation are in harmony.
5. The QC department should generate or review records for deviations and failure investigations. As batches are produced, it is important that all deviations from the normal manufacturing procedure are recorded or documented. Any impact on product quality must be assessed. It may be that additional product testing is required. It may be that additional stability testing is necessary.
6. Ingredients must comply with the qualitative and quantitative composition of the finished product as approved in the marketing authorization. It is most important that the materials used in manufacture comply with the details registered in the marketing authorization. It is on this basis that the product was developed and that all the stability testing has been carried out. All the clinical trials have also been completed using materials of a consistent specification. The product has been registered using those sources and quality of materials.
Module 4 Slide * of 11
Quality
production conditions
Basic Principles of GMP
In this section of the programme we are going to address all the issues relating to the quality management of pharmaceutical manufacturing.
Note for the Trainer: these times are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly.
The programme is approximately as follows:
Presentation 30 minutes
Group session I 20 minutes with 20 minutes for feedback
Presentation 30 minutes
Group session II 30 minutes with 30 minutes feed back
Test paper 45 minutes
The timing for the test paper allows 25 minutes for the test itself and the remaining time for a review of the answers.
The timing is flexible since this is a very important area. We want to ensure that the participants really understand this subject.
Module 4 Slide * of 11
Quality
GMP
Diminishes risks that cannot be controlled by testing of product
Cross-contamination
Mix-ups
Good Manufacturing Practice (GMP) is the part of quality assurance that ensures that products are produced and controlled consistently and reliably. This consistency of production and control is essential. It can only come about by having clear descriptions of the way in which the work will be done.
GMP specifically addresses risks that cannot be fully controlled by testing of the final product:
Cross-contamination
Mix-ups
These risks can best be controlled by having a properly managed system of working that takes them into account. This means that there must be good design, sound operation, and planned maintenance of facilities. It also means that the quality checking system must be designed with these risks in mind and set out to find whether any errors have occurred. Let us look at this problem in another way. If we do not know what sort of cross contamination we have, then the work of the analyst is very difficult. The analyst should ideally know what to test for before commencing testing. In other words, if we do not know what the likely cross-contaminant is then we cannot analyse for it.
There are a number of basic requirements for GMP, which we shall look at next.
Module 4 Slide * of 11
Quality
Critical steps validated
Trained operators
Basic requirements for GMP are as follows:
1. Clearly defined and systematically reviewed manufacturing processes. This means that all batch documentation, all quality specifications and all relevant SOPs must be prepared in harmony with one another. It also means that all departments involved must be aware of the work of the other departments in order to eliminate discrepancies. Finally, the quality control staff acting as the overall coordinator of all these activities should be involved in all decisions related to the quality of the production. It is their responsibility to ensure that the activities are aimed at producing products that meet the required specifications. The specifications are approved by the drug regulatory authority.
2. Critical steps of production processes are validated. Since there is variability in the quality of materials and in the performance of the equipment, we need to check whether the process works with all the variability that can arise. This process of checking and documenting variability is known as validation. It means that the company must have sufficient knowledge of its materials, equipment and processes that it knows what variables are likely to arise. It can then carry out controlled experiments to ensure that whatever variables do occur, they can still produce products meeting specifications. Validation is also required if there is a change in any part of the process, materials or equipment used in the manufacturing.
3. Appropriate resources: personnel, buildings, equipment and materials are available to produce a quality product. This means that the company has evaluated all of the elements it needs to produce a product and has sufficient resources of the right quality for its production.
4. Manufacturing is based on clearly written procedures. The procedures referred to here include the batch manufacturing and testing instructions and the SOPs needed for every department. Preparing these procedures and documents is a very important task that needs careful thought. The module on documentation goes into this in more detail.
5. Operators are trained. A company can have "all the documentation in the world" but if its operators are not properly trained to carry out the tasks that they are supposed to perform then the company will not be successful. We will talk more about this in the session on personnel. Operators not only need initial training but also follow-up training.
Module 4 Slide * of 11
Quality
QC / QA is part of GMP
The following QC slides illustrate that quality control is part of good manufacturing practice.
There is a handout to accompany these slides on quality control.
Module 4 Slide * of 11
Quality
Independent from production and other departments is considered to be fundamental
Under the authority of an appropriately qualified and experienced person with one or several control laboratories at his or her disposal.
Each holder of a manufacturing authorization should have a quality control department (except for a holder performing only a fraction of the manufacturing process under a contract).
The independence of quality control from production is considered fundamental. The quality control department should be independent fromother departments and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal.
Module 4 Slide * of 11
Quality
Resources
The quality control department must have adequate resources.
This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
Quality
Responsibilities
Testing
Sampling
Inspecting
Monitoring of all materials and environmental conditions in the factory
Releasing or rejecting materials for production use and finished products
Module 4 Slide * of 11
Quality
Establish QC procedures
Reference standards availability
Stability testing
Complaint investigations
Environmental monitoring
In addition to those already mentioned, the QC department has other duties to carry out, including:
1. Establishing, validating and implementing all QC procedures. All QC procedures need not only to be established in the first instance but also to undergo exactly the same critical review and maintenance process as operating procedures in all other areas.
2. Evaluating, maintaining, storing reference standards. Reference standards are among the most critical materials that QC has to handle. After all, the results of much testing rely upon comparison with an analytical reference standard. If that reference standard has not been looked after properly then all the test results may be incorrect.
3. Ensuring correct labelling of containers of materials and products. We have already mentioned just how critical this activity is. The major difficulty is the problem of seeing that an error has occurred. You are looking at a situation where there are thousands of components often being processed at high speed. It is nearly impossible for operators to see that an error has occurred. Systems must be in operation as the main safeguard. If equipment such as bar code readers are in operation it must be regularly checked for effectiveness.
4. Stability testing of active ingredients and finished products. A stability-testing programme should be developed for all products, described in the form of an SOP. Stability of active pharmaceutical ingredients should be monitored. Active ingredients should be regularly tested within their shelf-life to confirm suitability for continued use. The quality control department should have a very clear role in ensuring that samples are taken for the ongoing stability testing programme and that analysis is undertaken at the right time.
5. Participating in complaint investigations. We will be devoting a whole module to the importance of complaint and recall handling. It is worth repeating that complaints offer an opportunity for the company to learn from mistakes or product design failures. In this way actions can be taken to prevent re-occurrence.
6. Participating in environmental monitoring. There are many sides to environmental monitoring. With regard to products, the environment that we are referring to here is that which can immediately affect product quality. E.g.., swab testing and settle plates in a sterile area, testing of temperature and humidity control. There is another environment that needs to be looked at. External environment checks may be needed.
Module 4 Slide * of 11
Quality
Resources
This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
Quality
Sampling
Records
Failure investigations for all deviations / incidents
Ingredients comply with the marketing authorization
Ingredients are of the required purity / quality
Proper containers
Correct labelling
Any changes to written procedures, systems equipments should be handled
Let’s look at some of these basic requirements for quality control in greater detail:
1. Sampling should be undertaken by methods and personnel approved by the QC department. We described a little earlier the key issues around sampling. It is not a requirement that all sampling needs to be done by quality assurance or quality control personnel. The important point is that it is carried out in such a way that it is representative of the batch and in accordance with an SOP. QC personnel must have access to the production area to undertake sampling when necessary.
2. Validated test methods should be applied. The validation of test methods includes verification of: accuracy, precision, linearity, repeatability, robustness, specificity. This means that the test methods should be challenged to be able to demonstrate that the tests are able to give an accurate result on a repeatable basis. The methods must be capable of being applied with precision. The results obtained must be linear over a range of acceptable responses. Finally, the results must be repeatable over a number of identical tests.
3. Records for sampling, inspecting, testing of materials, intermediates and bulk and finished products need to be kept. It is essential too that the inspector assesses the records of the work done during processing. This means that there will be traceability on what happened.
4. The QC department should review and evaluate the relevant production documentation. This review needs to cover all quality aspects. As part of the documentation procedure, it is important that the quality control department approves all the documentation. This ensures that the manufacturing documentation and the quality assurance documentation are in harmony.
5. The QC department should generate or review records for deviations and failure investigations. As batches are produced, it is important that all deviations from the normal manufacturing procedure are recorded or documented. Any impact on product quality must be assessed. It may be that additional product testing is required. It may be that additional stability testing is necessary.
6. Ingredients must comply with the qualitative and quantitative composition of the finished product as approved in the marketing authorization. It is most important that the materials used in manufacture comply with the details registered in the marketing authorization. It is on this basis that the product was developed and that all the stability testing has been carried out. All the clinical trials have also been completed using materials of a consistent specification. The product has been registered using those sources and quality of materials.
Module 4 Slide * of 11
Quality
production conditions