1 3 gmp purpose principles guidelines
DESCRIPTION
GMPTRANSCRIPT
Slide 1Tony Gould
Why GMP?
Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality
Medicines are manufactured to comply with their marketing authorization
Quality is built in
Testing is part of GMP, but alone does not provide a good level of quality assurance
* | PQ Workshop, Abu Dhabi | October 2010
Why inspect?
Verify compliance with marketing authorization
Dossier: "Dedicated equipment is used"
Inspection: Observation that this means "dedicated while used for the product or not being used for another product"
Dossier: "The vials are removed from the lyophilliser and crimped in a grade A environment"
Inspection: Correct, but before crimping they are stored in an uncontrolled corridor
* | PQ Workshop, Abu Dhabi | October 2010
WHO GMP
Volume 2, 2nd updated edition
Good manufacturing practices
Guidelines and references
GMP applies to both Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs)
FPP:
API:
*
Other WHO GMP Guidelines
Investigational pharmaceutical products for clinical trials i
Herbal medicinal products
Validation
Good Manufacturing Practices (FPP):
3. Sanitation and hygiene
4. Qualification and validation
General
Good Manufacturing Practices (cont'd)
Items for self-inspection
Good Manufacturing Practices (cont'd)
Good Manufacturing Practices (cont'd)
Recalled products
Returned goods
Good Manufacturing Practices (cont'd)
Specifications for starting and packaging materials, for intermediate and bulk products and for finished products
Master formulae and Batch Processing Records
Packaging instructions and Batch Packaging Records
Standard Operating procedures (SOP's) and records
Logbooks
Good Manufacturing Practices (cont'd)
General
Processing operations
Packaging operations
Control of starting materials and intermediate, bulk and finished products
Test requirements
Quality Management
Quality Assurance
Philosophy and essential elements:
"The concepts of quality assurance, GMP, quality control and quality risk management are interrelated aspects of quality management, and should be the responsibility of all personnel. ……their relationship and their fundamental importance to the production and control of pharmaceutical products."
Glossary
Quality Management
An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources
The systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality”
The totality of these actions is referred to as “Quality Assurance”
* | PQ Workshop, Abu Dhabi | October 2010
The five P's
Quality Assurance
Quality assurance is a management tool
In contractual situations, it also serves to generate confidence in a supplier
QA, GMP and Quality Control are interrelated aspects of Quality Management
They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products
1.1
Quality Assurance
Wide-ranging concept
covers all matters that individually or collectively influence the quality of a product
Totality of the arrangements
to ensure that the drug is continuously of the right quality for the intended use
Quality Assurance incorporates GMP
and also includes product design and development, with special focus on process design
1.1
The position of QA
Quality Assurance means to assure:
Products are designed and developed correctly
Complying with, e.g. GMP, GCP, GLP
Production and control operations are defined
Managerial responsibilities are defined
In job descriptions
The manufacture, supply and use of correct starting and packaging materials
1.1 a- d
Quality Assurance means to assure:
(cont'd)
Products are sold/supplied only after review by the authorized person
Complying with marketing authorization, production and QC requirements
Proper storage, distribution and handling
1.1 e - h
Quality Assurance means to assure:
(cont'd)
Deviations are reported, investigated and recorded
System for change control is applied
Regular evaluation of product quality to verify consistency and continued improvement
1.1 i - l
Quality Assurance includes:
Responsibility of the Manufacturer for the quality of the product
Fit for intended use
Comply with marketing authorization
Safety, efficacy and quality
Comprehensively designed and well implemented quality system
Full documentation and monitoring of effectiveness
Competent personnel, sufficient premises, equipment and facilities
1.3
Good Manufacturing Practices
That part of QA that ensures that products are consistently produced and controlled
Quality standards
Marketing authorization
Aim: Diminishing risks that cannot be controlled by testing of product
Contamination and cross-contamination
Basic requirements for GMP:
Qualification and validation is performed
Appropriate resources are provided:
Qualified and trained personnel
Materials, containers, labels
Procedures, storage, transport
Basic requirements for GMP: (cont'd)
Clear, written instructions and procedures
Trained operators
Records for manufacture and distribution
Proper storage and distribution
2.1 d - j
GMP = continuous urge for improvement
Involvement of the management
Annual Product Quality Review
Involvement of the management
The senior management is responsible to attain the company's quality objectives
All different departments and all levels within departments should be involved; and it's the senior management who should facilitate this
Also suppliers and distributors should be involved
The senior management should make available the required resources
The basis of the quality system is the quality statement and quality policy, by the senior management
* | PQ Workshop, Abu Dhabi | October 2010
Product Quality Review
Objectives of Product Quality Review:
To review and verify the consistency and appropriateness of the existing process
To identify and highlight any trends in the process, e.g. in analytical results, yields etc.
To identify any possible product or process improvements
* | PQ Workshop, Abu Dhabi | October 2010
Product Quality Review (cont'd)
Review of starting materials/ packaging materials, especially from new sources
Review of in-process control results and finished product analytical control results
Amount of batches and packaging units produced and their yields
Reviews of:
Plus investigations and analysis of causes
* | PQ Workshop, Abu Dhabi | October 2010
Annual Product Quality Review (cont'd)
Review of Marketing Authorization variations submitted, granted or refused (incl. third countries)
Review of stability programme and trends
Review of adequacy of previous decisions on changes or improvements or corrective actions
For new Marketing Authorizations (plus new variations) a review of post marketing commitment
The qualification status of all relevant equipment and utilities (like water, HVAC, gases, etc.)
Review of Technical Agreements (if applicable)
* | PQ Workshop, Abu Dhabi | October 2010
Complaints handling
Complaints: Principle
“All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures and corrective action should be taken.”
5.1
The product complaint principle is defined in the WHO GMP.
The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization, and do not place the patient at risk because of inadequate safety, quality or efficacy.
Complaints must be handled positively and carefully reviewed, and corrective actions must be taken as necessary. This can mean amending a manufacturing process as well as implementing a recall of a defective product from all markets where it has been distributed.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure
Decide on measure to be taken
May be authorized person - if not, must advise authorized person of results
Sufficient support staff
Access to records
Written procedure (SOP):
Includes need to consider a recall (e.g. possible product defect)
5.2 – 5.3
World Health Organization
First of all a written complaints handling procedure should be available.
The basic requirements for such a procedure are:
A designated person must be appointed with authority to conduct complaints reviews in accordance with the SOPs. The person designated may be the authorized person responsible for quality control. If not, then that QC person must be kept informed of all complaints being investigated. The designated person must have sufficient staff to be able to review all the complaints received in an effective and rapid manner. They must to be able to access all the relevant records concerning the product under discussion.
Required actions are described.
The complaint is acknowledged and a response to the customer is provided.
Written and verbal comments are recorded.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure – cont'd
Thorough investigation:
QC involved
With special attention to establish whether "counterfeiting" may have been the cause
Fully recorded investigation – reflect all the details
Due to product defect (discovered or suspected):
Consider checking other batches
Batches containing reprocessed product
World Health Organization
The QC department should be involved throughout the investigation. The investigation should be thorough and fully recorded– and reflect all the details of the investigation in the records.
Special attention must be given to try and establish whether "counterfeiting" may have been the cause.
If there is a product defect (discovered or suspected), then the company should consider checking other batches, and may have to check batches containing reprocessed product.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure – cont'd
May include a "recall"
Referenced in batch records
5.7 – 5.9
Investigation and evaluation should result in appropriate follow up actions taken. This may include a "recall" of the product, or batch.
All decisions and measures taken should be recorded.
The complaint should also be referenced in batch records – and may thus help during the review or annual product review, trend analysis etc.
Complaint records should be reviewed on a regular basis as defined in the SOP. Trends and recurring problems should be identified and proper action taken to prevent recurrence of the problem/cause. As complaints are investigated and records are built up, then trends may start to become clear. A regular review of complaint records to establish whether there is a trend for a particular product, dosage form, customer, distribution channel or similar should be undertaken. This is where the true value of a good complaints handling procedure shows. It may be that a particular formulation or particular machine is giving rise to complaints. This trend analysis process is an opportunity for continuous improvement.
It may be that a particular customer is engaged in fraudulent behaviour.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints - other actions
Inform competent authorities in case of serious quality problems such as:
Faulty manufacture
Product deterioration
Counterfeiting
Have a thorough recall procedure that is consistent with the complaints handling procedure
Trend complaints, their investigations and results
5.10
World Health Organization
The competent authority must be informed of any serious quality problems that are revealed by the complaint investigation
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection
Purpose is to evaluate whether a company’s operations remain compliant with GMP
The programme should
be designed to detect shortcomings in the implementation of GMP
recommend corrective actions
Should be performed routinely
Recalls
World Health Organization
The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control.
It also assists in ensuring quality improvement. There should be a programme that covers all aspects of production and quality control. It should be designed to detect shortcomings in the implementation of GMP and recommend corrective actions. The company should set a timetable for corrective action to be completed. You can verify this during your assessment.
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection (cont'd)
authority
sufficient experience, expertise in their own field. knowledge of GMP
may be from inside or outside the company
Frequency should normally be at least once a year
May depend on company requirements
Size of the company and activities
8.3, 8.4
World Health Organization
The self-inspection team is appointed by the management of the company and is made up of a mixture of people, including experts in GMP and persons familiar with the area to be inspected. It is useful to have people from production, QC and engineering on the team, as they will bring different perspectives to the inspection.
The team leader needs to be someone who has access to the resources to produce a report at the end of the process, and with the authority and experience to organize and manage a team activity. Hence it is usually, but not always, a manager or supervisor.
The leader should be from a different department so that he/she can take a more impartial viewpoint.
It is important that the team members are encouraged to be objective in their evaluation.
The frequency with which self-inspections are carried out will depend on the company. For a small company that can cover all its operations in one inspection, a three or six-monthly review might be sufficient. However, for a larger company that needs to split the inspection into a number of sections, a programme of monthly inspections covering the whole factory in three to six months might be more appropriate.
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection (cont'd)
results
evaluation
conclusions
8.5, 8.6
World Health Organization
All inspections need reports as an outcome; otherwise there is no formal record of the findings and recommendations.
This report should be issued as quickly as possible while things are fresh in people’s minds. It does not need to be an elaborate, wordy document that no one will read. A simple list of findings with recommendations for corrective action is sufficient. However, it is important that responsibility for action and a time frame are agreed, either during the inspection or soon after the report is issued.
A self-inspection without follow-up is unlikely to be particularly effective and it is important that the company management ensures that the corrective measures are carried out to the agreed timetable.
* | PQ Workshop, Abu Dhabi | October 2010
Summary and conclusions:
Quality should be built into the product
GMP's are very similar and are really Good Common Sense
Good Practices cover all aspects of manufacturing activities prior to supply
The role and involvement of senior management is crucial
* | PQ Workshop, Abu Dhabi | October 2010
http://www.who.int/prequal
Why GMP?
Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality
Medicines are manufactured to comply with their marketing authorization
Quality is built in
Testing is part of GMP, but alone does not provide a good level of quality assurance
* | PQ Workshop, Abu Dhabi | October 2010
Why inspect?
Verify compliance with marketing authorization
Dossier: "Dedicated equipment is used"
Inspection: Observation that this means "dedicated while used for the product or not being used for another product"
Dossier: "The vials are removed from the lyophilliser and crimped in a grade A environment"
Inspection: Correct, but before crimping they are stored in an uncontrolled corridor
* | PQ Workshop, Abu Dhabi | October 2010
WHO GMP
Volume 2, 2nd updated edition
Good manufacturing practices
Guidelines and references
GMP applies to both Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs)
FPP:
API:
*
Other WHO GMP Guidelines
Investigational pharmaceutical products for clinical trials i
Herbal medicinal products
Validation
Good Manufacturing Practices (FPP):
3. Sanitation and hygiene
4. Qualification and validation
General
Good Manufacturing Practices (cont'd)
Items for self-inspection
Good Manufacturing Practices (cont'd)
Good Manufacturing Practices (cont'd)
Recalled products
Returned goods
Good Manufacturing Practices (cont'd)
Specifications for starting and packaging materials, for intermediate and bulk products and for finished products
Master formulae and Batch Processing Records
Packaging instructions and Batch Packaging Records
Standard Operating procedures (SOP's) and records
Logbooks
Good Manufacturing Practices (cont'd)
General
Processing operations
Packaging operations
Control of starting materials and intermediate, bulk and finished products
Test requirements
Quality Management
Quality Assurance
Philosophy and essential elements:
"The concepts of quality assurance, GMP, quality control and quality risk management are interrelated aspects of quality management, and should be the responsibility of all personnel. ……their relationship and their fundamental importance to the production and control of pharmaceutical products."
Glossary
Quality Management
An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources
The systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality”
The totality of these actions is referred to as “Quality Assurance”
* | PQ Workshop, Abu Dhabi | October 2010
The five P's
Quality Assurance
Quality assurance is a management tool
In contractual situations, it also serves to generate confidence in a supplier
QA, GMP and Quality Control are interrelated aspects of Quality Management
They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products
1.1
Quality Assurance
Wide-ranging concept
covers all matters that individually or collectively influence the quality of a product
Totality of the arrangements
to ensure that the drug is continuously of the right quality for the intended use
Quality Assurance incorporates GMP
and also includes product design and development, with special focus on process design
1.1
The position of QA
Quality Assurance means to assure:
Products are designed and developed correctly
Complying with, e.g. GMP, GCP, GLP
Production and control operations are defined
Managerial responsibilities are defined
In job descriptions
The manufacture, supply and use of correct starting and packaging materials
1.1 a- d
Quality Assurance means to assure:
(cont'd)
Products are sold/supplied only after review by the authorized person
Complying with marketing authorization, production and QC requirements
Proper storage, distribution and handling
1.1 e - h
Quality Assurance means to assure:
(cont'd)
Deviations are reported, investigated and recorded
System for change control is applied
Regular evaluation of product quality to verify consistency and continued improvement
1.1 i - l
Quality Assurance includes:
Responsibility of the Manufacturer for the quality of the product
Fit for intended use
Comply with marketing authorization
Safety, efficacy and quality
Comprehensively designed and well implemented quality system
Full documentation and monitoring of effectiveness
Competent personnel, sufficient premises, equipment and facilities
1.3
Good Manufacturing Practices
That part of QA that ensures that products are consistently produced and controlled
Quality standards
Marketing authorization
Aim: Diminishing risks that cannot be controlled by testing of product
Contamination and cross-contamination
Basic requirements for GMP:
Qualification and validation is performed
Appropriate resources are provided:
Qualified and trained personnel
Materials, containers, labels
Procedures, storage, transport
Basic requirements for GMP: (cont'd)
Clear, written instructions and procedures
Trained operators
Records for manufacture and distribution
Proper storage and distribution
2.1 d - j
GMP = continuous urge for improvement
Involvement of the management
Annual Product Quality Review
Involvement of the management
The senior management is responsible to attain the company's quality objectives
All different departments and all levels within departments should be involved; and it's the senior management who should facilitate this
Also suppliers and distributors should be involved
The senior management should make available the required resources
The basis of the quality system is the quality statement and quality policy, by the senior management
* | PQ Workshop, Abu Dhabi | October 2010
Product Quality Review
Objectives of Product Quality Review:
To review and verify the consistency and appropriateness of the existing process
To identify and highlight any trends in the process, e.g. in analytical results, yields etc.
To identify any possible product or process improvements
* | PQ Workshop, Abu Dhabi | October 2010
Product Quality Review (cont'd)
Review of starting materials/ packaging materials, especially from new sources
Review of in-process control results and finished product analytical control results
Amount of batches and packaging units produced and their yields
Reviews of:
Plus investigations and analysis of causes
* | PQ Workshop, Abu Dhabi | October 2010
Annual Product Quality Review (cont'd)
Review of Marketing Authorization variations submitted, granted or refused (incl. third countries)
Review of stability programme and trends
Review of adequacy of previous decisions on changes or improvements or corrective actions
For new Marketing Authorizations (plus new variations) a review of post marketing commitment
The qualification status of all relevant equipment and utilities (like water, HVAC, gases, etc.)
Review of Technical Agreements (if applicable)
* | PQ Workshop, Abu Dhabi | October 2010
Complaints handling
Complaints: Principle
“All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures and corrective action should be taken.”
5.1
The product complaint principle is defined in the WHO GMP.
The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization, and do not place the patient at risk because of inadequate safety, quality or efficacy.
Complaints must be handled positively and carefully reviewed, and corrective actions must be taken as necessary. This can mean amending a manufacturing process as well as implementing a recall of a defective product from all markets where it has been distributed.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure
Decide on measure to be taken
May be authorized person - if not, must advise authorized person of results
Sufficient support staff
Access to records
Written procedure (SOP):
Includes need to consider a recall (e.g. possible product defect)
5.2 – 5.3
World Health Organization
First of all a written complaints handling procedure should be available.
The basic requirements for such a procedure are:
A designated person must be appointed with authority to conduct complaints reviews in accordance with the SOPs. The person designated may be the authorized person responsible for quality control. If not, then that QC person must be kept informed of all complaints being investigated. The designated person must have sufficient staff to be able to review all the complaints received in an effective and rapid manner. They must to be able to access all the relevant records concerning the product under discussion.
Required actions are described.
The complaint is acknowledged and a response to the customer is provided.
Written and verbal comments are recorded.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure – cont'd
Thorough investigation:
QC involved
With special attention to establish whether "counterfeiting" may have been the cause
Fully recorded investigation – reflect all the details
Due to product defect (discovered or suspected):
Consider checking other batches
Batches containing reprocessed product
World Health Organization
The QC department should be involved throughout the investigation. The investigation should be thorough and fully recorded– and reflect all the details of the investigation in the records.
Special attention must be given to try and establish whether "counterfeiting" may have been the cause.
If there is a product defect (discovered or suspected), then the company should consider checking other batches, and may have to check batches containing reprocessed product.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints Procedure – cont'd
May include a "recall"
Referenced in batch records
5.7 – 5.9
Investigation and evaluation should result in appropriate follow up actions taken. This may include a "recall" of the product, or batch.
All decisions and measures taken should be recorded.
The complaint should also be referenced in batch records – and may thus help during the review or annual product review, trend analysis etc.
Complaint records should be reviewed on a regular basis as defined in the SOP. Trends and recurring problems should be identified and proper action taken to prevent recurrence of the problem/cause. As complaints are investigated and records are built up, then trends may start to become clear. A regular review of complaint records to establish whether there is a trend for a particular product, dosage form, customer, distribution channel or similar should be undertaken. This is where the true value of a good complaints handling procedure shows. It may be that a particular formulation or particular machine is giving rise to complaints. This trend analysis process is an opportunity for continuous improvement.
It may be that a particular customer is engaged in fraudulent behaviour.
* | PQ Workshop, Abu Dhabi | October 2010
Complaints - other actions
Inform competent authorities in case of serious quality problems such as:
Faulty manufacture
Product deterioration
Counterfeiting
Have a thorough recall procedure that is consistent with the complaints handling procedure
Trend complaints, their investigations and results
5.10
World Health Organization
The competent authority must be informed of any serious quality problems that are revealed by the complaint investigation
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection
Purpose is to evaluate whether a company’s operations remain compliant with GMP
The programme should
be designed to detect shortcomings in the implementation of GMP
recommend corrective actions
Should be performed routinely
Recalls
World Health Organization
The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control.
It also assists in ensuring quality improvement. There should be a programme that covers all aspects of production and quality control. It should be designed to detect shortcomings in the implementation of GMP and recommend corrective actions. The company should set a timetable for corrective action to be completed. You can verify this during your assessment.
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection (cont'd)
authority
sufficient experience, expertise in their own field. knowledge of GMP
may be from inside or outside the company
Frequency should normally be at least once a year
May depend on company requirements
Size of the company and activities
8.3, 8.4
World Health Organization
The self-inspection team is appointed by the management of the company and is made up of a mixture of people, including experts in GMP and persons familiar with the area to be inspected. It is useful to have people from production, QC and engineering on the team, as they will bring different perspectives to the inspection.
The team leader needs to be someone who has access to the resources to produce a report at the end of the process, and with the authority and experience to organize and manage a team activity. Hence it is usually, but not always, a manager or supervisor.
The leader should be from a different department so that he/she can take a more impartial viewpoint.
It is important that the team members are encouraged to be objective in their evaluation.
The frequency with which self-inspections are carried out will depend on the company. For a small company that can cover all its operations in one inspection, a three or six-monthly review might be sufficient. However, for a larger company that needs to split the inspection into a number of sections, a programme of monthly inspections covering the whole factory in three to six months might be more appropriate.
* | PQ Workshop, Abu Dhabi | October 2010
Self-Inspection (cont'd)
results
evaluation
conclusions
8.5, 8.6
World Health Organization
All inspections need reports as an outcome; otherwise there is no formal record of the findings and recommendations.
This report should be issued as quickly as possible while things are fresh in people’s minds. It does not need to be an elaborate, wordy document that no one will read. A simple list of findings with recommendations for corrective action is sufficient. However, it is important that responsibility for action and a time frame are agreed, either during the inspection or soon after the report is issued.
A self-inspection without follow-up is unlikely to be particularly effective and it is important that the company management ensures that the corrective measures are carried out to the agreed timetable.
* | PQ Workshop, Abu Dhabi | October 2010
Summary and conclusions:
Quality should be built into the product
GMP's are very similar and are really Good Common Sense
Good Practices cover all aspects of manufacturing activities prior to supply
The role and involvement of senior management is crucial
* | PQ Workshop, Abu Dhabi | October 2010
http://www.who.int/prequal