Basic Principles of GMP 4. Complaints and Product recall

Product complaint 1 Ideally, every batch manufacture is a success We do not live in an ideal World i.e. there will be manufacturing failures

Product complaint 2 some of them will not be identified within the company i.e., there will be inevitably complaints there should be a complaint handling policy… …that may cover also recalls

Complaints Handling Principle 1 All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures Quality management is defined in the WHO GMP. One necessary but not always pleasant aspect of quality management is dealing with complaints. It is important that complaints are handled in accordance with a written procedure, and that the results of the investigation are used to improve the situation and prevent recalls and complaints in the future. Complaints must be handled positively and be carefully reviewed. The handling of complaints must be seen by all areas of the company as being important work, which is the responsibility of a senior staff member. Thorough investigation of the cause for the complaint is essential before decisions can be taken as to how it should be resolved. Complaints can be an important source information and learning for the company and enable potentially serious defects to be remedied before they become so serious as to initiate a recall. Actions must be taken as necessary, possibly even leading to a recall decision.

Complaints Handling Principle 2 Handled positively and carefully reviewed Must be seen as important work Managed by a senior staff member Thorough investigation of the cause is essential Quality management is defined in the WHO GMP. One necessary but not always pleasant aspect of quality management is dealing with complaints. It is important that complaints are handled in accordance with a written procedure, and that the results of the investigation are used to improve the situation and prevent recalls and complaints in the future. Complaints must be handled positively and be carefully reviewed. The handling of complaints must be seen by all areas of the company as being important work, which is the responsibility of a senior staff member. Thorough investigation of the cause for the complaint is essential before decisions can be taken as to how it should be resolved. Complaints can be an important source information and learning for the company and enable potentially serious defects to be remedied before they become so serious as to initiate a recall. Actions must be taken as necessary, possibly even leading to a recall decision.

Complaints Handling Principle 3 All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures (cont’d) A major source of information and learning Enable possible production defects to be remedied before they lead to a recall. Necessary actions taken -- even a recall decision Quality management is defined in the WHO GMP. One necessary but not always pleasant aspect of quality management is dealing with complaints. It is important that complaints are handled in accordance with a written procedure, and that the results of the investigation are used to improve the situation and prevent recalls and complaints in the future. Complaints must be handled positively and be carefully reviewed. The handling of complaints must be seen by all areas of the company as being important work, which is the responsibility of a senior staff member. Thorough investigation of the cause for the complaint is essential before decisions can be taken as to how it should be resolved. Complaints can be an important source information and learning for the company and enable potentially serious defects to be remedied before they become so serious as to initiate a recall. Actions must be taken as necessary, possibly even leading to a recall decision.

Complaints Procedure - I Designated responsible person May be the authorized person If not, must advise authorized person of results Sufficient support staff Access to records Written procedure describing action to be taken Acknowledge and respond to complainant within a reasonable period Record written and verbal comments 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.

Complaints Procedure - II Investigate and review QA should review complaint Appropriate follow up actions Review of trends Written complaints handling procedure (continued). Investigations and reviews are done as a result of a complaint. Complaints are reviewed on a regular basis by the QC/QA department. Appropriate follow-up actions are taken. These will be both corrective and preventative and may include reviewing of other batches of the product. Trends of complaints should be reviewed.

Records of Complaint Investigation Complaints Records of Complaint Investigation Name of product Name of active substance (INN) if necessary Strength, dosage form Batch number Name of complainant and nature of complaint (cont’d) Besides the complaints procedure itself, records should be kept to document each incident. The records should be kept for the time specified in the procedure. It must be emphasized that: 1. The investigation process is extremely important. 2. Action taken to prevent reoccurrence is also important. The records should contain: Product name, Active ingredient name INN if necessary, (paper on INN at http://noc.aic.net/inet98/8x/8x_2.htm#s7), strength, dosage form Batch number Name of complainant Nature of complaint Records investigated and the details recorded from these documents. Staff interviewed Result of investigation — is the complaint justified or not justified? Actions taken Sign-off upon completion. This record can then be used by staff in authority to change the necessary processes within manufacturing or quality assurance to ensure that the cause of the complaint does not arise again. It may be necessary to consider whether other batches should be checked to see if they too should be subject to detailed investigation. The investigation should be thorough enough to identify the fundamental cause of the complaint. Only then will the opportunity arise for corrective action to be taken.

Records of Complaint Investigation Complaints Records of Complaint Investigation Records, retention sample investigated, other batches reviewed and staff interviewed Result of investigation: “Justified” or “Not justified” If “justified”, actions taken to prevent reoccurrence Sign-off upon completion Besides the complaints procedure itself, records should be kept to document each incident. The records should be kept for the time specified in the procedure. It must be emphasized that: 1. The investigation process is extremely important. 2. Action taken to prevent reoccurrence is also important. The records should contain: Product name, Active ingredient name INN if necessary, (paper on INN at http://noc.aic.net/inet98/8x/8x_2.htm#s7), strength, dosage form Batch number Name of complainant Nature of complaint Records investigated and the details recorded from these documents. Staff interviewed Result of investigation — is the complaint justified or not justified? Actions taken Sign-off upon completion. This record can then be used by staff in authority to change the necessary processes within manufacturing or quality assurance to ensure that the cause of the complaint does not arise again. It may be necessary to consider whether other batches should be checked to see if they too should be subject to detailed investigation. The investigation should be thorough enough to identify the fundamental cause of the complaint. Only then will the opportunity arise for corrective action to be taken.

Decision from a Complaint Investigation Complaints Decision from a Complaint Investigation Complaint justified Actions to prevent reoccurrence Ongoing observation of process Recall product may be required Complaint not justified Advise customer of findings Appropriate marketing response There are 2 decisions possible when a complaint has been evaluated. The first is that the complaint is justified. In this case the company should have developed a plan of action that should work towards eliminating the cause of the problems. In addition, there should be a plan for observation of product performance to ensure that the defect does not arise again. The second possible decision is that the complaint is not justified. For example, when the product has expired for a long time or the product was not kept at the storage conditions stated by the manufacturers.

Complaints Other issues Regular review of trends required Reoccurring problems Potential recall or withdrawal Inform competent authority of serious quality problems 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. The competent authority must be informed of any serious quality problems that are revealed by the complaint investigation Let us now move on to look at recall procedures.

Classification of Defects Complaints Classification of Defects If complaint is justified, then there has been a failure of the quality system Once defect has been identified, company should be dealing with it in an appropriate way, even recall The definition of defects is useful (cont’d) During complaints handling and especially in recall situations it is important to have clear guidance to define the magnitude of the problem. If an investigation into a complaint proves that the complaint is justified, then there has been a failure of the quality system resulting in a defective product becoming available. Once a very serious defect has been identified, it is important to be sure that the company is dealing with the recall in an appropriate way. How quickly should the company be responding to the problem? The definition of defects therefore is important. We are suggesting here a system of classification that may be helpful. Some countries have different approaches. This system has been in use in a number of countries and found to be useful. Classification of defects: Critical defects Major defects Other defects. This is a very difficult area requiring professional judgement in coming to the correct decision. The company should have procedures to call into operation to decide whether a recall is required and how quickly it should be implemented. These procedures should be discussed and agreed with the regulatory authority.

Classification of Defects Complaints Classification of Defects The following system has been found in some countries (but it is not a WHO guideline): Critical defects Major defects Other defects During complaints handling and especially in recall situations it is important to have clear guidance to define the magnitude of the problem. If an investigation into a complaint proves that the complaint is justified, then there has been a failure of the quality system resulting in a defective product becoming available. Once a very serious defect has been identified, it is important to be sure that the company is dealing with the recall in an appropriate way. How quickly should the company be responding to the problem? The definition of defects therefore is important. We are suggesting here a system of classification that may be helpful. Some countries have different approaches. This system has been in use in a number of countries and found to be useful. Classification of defects: Critical defects Major defects Other defects. This is a very difficult area requiring professional judgement in coming to the correct decision. The company should have procedures to call into operation to decide whether a recall is required and how quickly it should be implemented. These procedures should be discussed and agreed with the regulatory authority.

Complaints Critical Defects Those defects which can be life threatening and require the company to take immediate action by all reasonable means, whether in or out of business hours Examples (next slide) Critical defects are those defects which can be life-threatening and which require the company to take immediate action by all reasonable means, as soon as the defect becomes apparent, whether in or out of business hours. This means that all wholesalers must be alerted and the necessary actions taken to commence recalling the product throughout the distribution chain. This illustrates how important distribution records are, including those of the wholesaler. Examples of critical defects are: Product labelled with incorrect name Counterfeit or deliberately tampered with product Microbiological contamination of a sterile product. It can be seen from the examples that it is critical to patient health that immediate action is taken. It may mean using radio and television news broadcasts to conduct the recall.

Complaints Critical Defects Examples Product labelled with incorrect name or incorrect strength Counterfeit or deliberately tampered-with product Microbiological contamination of a sterile product Critical defects are those defects which can be life-threatening and which require the company to take immediate action by all reasonable means, as soon as the defect becomes apparent, whether in or out of business hours. This means that all wholesalers must be alerted and the necessary actions taken to commence recalling the product throughout the distribution chain. This illustrates how important distribution records are, including those of the wholesaler. Examples of critical defects are: Product labelled with incorrect name Counterfeit or deliberately tampered with product Microbiological contamination of a sterile product. It can be seen from the examples that it is critical to patient health that immediate action is taken. It may mean using radio and television news broadcasts to conduct the recall.

Complaints Major Defects Those defects which may put the patient at some risk but are not life threatening and will require the batch recall or product withdrawal within a few days Examples (next dia) Major defects are those defects which may put the patient at some risk but which are not life-threatening. They will require the recall of the batch or product withdrawal within a few days. In some countries this is specified as within 48 hours. Examples of major defects are: Any labelling/leaflet misinformation (or lack of information) which represents a significant hazard to the patient Microbial contamination of non-sterile products with some risks Non-compliance to specifications (e.g. active ingredient assay close to limits but out of specification). A country may decide on different time-scales for recalls, depending on the appropriate response for the product or defect concerned.

Complaints Major Defects Examples Any labelling/leaflet misinformation (or lack of information) which represents a significant hazard to the patient Microbial contamination of non-sterile products with some risk for patients Non-compliance to specifications (e.g. active ingredient assay) Major defects are those defects which may put the patient at some risk but which are not life-threatening. They will require the recall of the batch or product withdrawal within a few days. In some countries this is specified as within 48 hours. Examples of major defects are: Any labelling/leaflet misinformation (or lack of information) which represents a significant hazard to the patient Microbial contamination of non-sterile products with some risks Non-compliance to specifications (e.g. active ingredient assay close to limits but out of specification). A country may decide on different time-scales for recalls, depending on the appropriate response for the product or defect concerned.

Complaints Other Defects Those defects which present only a minor risk to the patient — batch recall or product withdrawal would normally be initiated within a few days Examples (next dia) Other defects are those defects which present only a minor risk to the patient. Any batch recall or product withdrawal would normally be initiated within a few days. In some countries this is specified as within five working days. Examples of such defect are: Readily visible isolated packaging/closure faults Contamination which may cause spoilage or dirt and where there is minimal risk to the patient. Again this shows a less speedy response to the situation which is in balance with the level of risk for the patient. Let us summarize at this point: It is important that complaints as well as potential recall situations result in the proper categorization of the problem. This means that the company will then undertake recalls or complaints handling with the correct level of urgency and not unduly alarm patients or the public. It is essential that the public retain a high level of confidence in the supply of pharmaceuticals. This confidence, however, must be justified.

Complaints Other Defects Examples Readily visible isolated packaging/closure faults Contamination which may cause spoilage or dirt and where there is minimal risk to the patient Other defects are those defects which present only a minor risk to the patient. Any batch recall or product withdrawal would normally be initiated within a few days. In some countries this is specified as within five working days. Examples of such defect are: Readily visible isolated packaging/closure faults Contamination which may cause spoilage or dirt and where there is minimal risk to the patient. Again this shows a less speedy response to the situation which is in balance with the level of risk for the patient. Let us summarize at this point: It is important that complaints as well as potential recall situations result in the proper categorization of the problem. This means that the company will then undertake recalls or complaints handling with the correct level of urgency and not unduly alarm patients or the public. It is essential that the public retain a high level of confidence in the supply of pharmaceuticals. This confidence, however, must be justified.

Product Recall Principle Recalls Product Recall Principle “There should be a system to recall from the market promptly and effectively, products known or suspected to be defective.” (WHO GMP) The product recall 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. Recalls must be handled positively and carefully reviewed, and actions must be taken as necessary leading to an effective recall of defective product from all markets where it has been distributed.

Recalls Reasons for Recall Customer complaint Detection of GMP failure after release Result from the ongoing stability testing Order of the national authorities Result of an inspection Known counterfeiting or tampering Adverse reaction reporting A recall situation can result from information entering a company in various ways: Customer complaints – these may be so serious as to initiate a recall. An example could be the evidence of a lack of sterility GMP deviations/results of a failure investigation The result from the QC stability programme Request by the regulatory authorities Result of an inspection Known counterfeiting or tampering Adverse drug reaction (ADR) reported, leading to a recall decision (however, an ADR does not automatically lead to a recall). The company must have a procedure in place that can be operated at all hours to decide how serious a defect is and whether it warrants a recall.

Detection of GMP failure Recalls Detection of GMP failure The photo shows an active tablet in the row of placebos in a bi-phasic oral contraceptive blister pack An example of a defect that can lead to a recall

EXAMPLE „the same” tablets in the same pack

EXAMPLE: „the same” coated tablets

EXAMPLE: an ointment if we have a look inside…

the same ointment, magnified

Recalls Definition Recall Removal from the market of specified batches of a product May refer to one batch or all batches of product To deal with the topic of recalls we should first review some definitions: Recall is the removal from the market of specified batches or all batches of a product. Some countries refer to the recall of all batches as “withdrawal”.

Designated Responsible Recall Person Recalls Designated Responsible Recall Person May be the authorized person If not, must advise authorized person of results Sufficient support staff for urgency of recall Independent of sales and marketing Access to records A designated person must be appointed with authority to conduct recalls in accordance with the procedures. The person designated may be the authorized person responsible for quality control. If not then that QC person must be kept informed of all recalls being conducted. The designated person must have sufficient staff to be able to undertake recalls in an effective and rapid manner with appropriate urgency. The designated person should normally be independent of sales and marketing departments and must have the status and authority to be able to carry out the procedure.

Recalls SOP for Recall Established, authorized Actions to be taken Regularly checked and updated Capable of rapid operation to hospital and pharmacy level Communication concept to national authorities and internationally The recall procedure must be written, authorized by at least the quality control manager, describe clearly the actions to be taken, and include a requirement that it is regularly checked and updated. It must be capable of rapid start-up, out of business hours if necessary. It should include a communications plan to enable all key personnel, and deputies in case of absence, to be contacted outside normal business hours. It is essential that all the authorities in all the countries to which the relevant batch or batches have been sent are informed of the recall. This contact may be done at government level (government-to-government) but not necessarily. It is the manufacturer’s responsibility to ensure that the competent authorities in each country are informed. The manufacturer should also inform importers of the product. The importers will probably be the holders of any product registration and will also know where the product has been distributed. Key contact telephone numbers for all authorities that may need to be contacted should be listed.

Recalls Distribution Records Available to designated person for recall purposes Accurate Include information on: Wholesalers Direct customers (if any) Batch numbers Quantities Essential to the success of any recall is the quality of information contained in distribution records. The company is required to maintain in its records, accurate information on the quantity and batch number of any product it sends to wholesalers or its own direct customers. Full details must be kept of the names, addresses and telephone numbers of all customers. This point raises issues about the records that must be kept by distributors. We have plenty of examples where distributors fail to keep records that can be essential for a product recall. National authorities and manufacturers must continue to exercise pressure to ensure that distributors maintain records at batch number level.

Written progress report and reconciliation Recalls Written progress report and reconciliation Record progress as procedure followed Reconcile delivered with recovered products Issue final report As the recall progresses in accordance with the written procedure, written progress reports must be kept showing that all stages of the recall procedure have been adhered to. A reconciliation must also be prepared, showing the total product quantity distributed and the total quantity returned, by batch. It should identify any areas where reconciliation has not been achieved and offer reasons why. A final report must be issued to cover all aspects of the recalls including lessons to be learnt for the future conduct of such recalls. The effectiveness of SOP must also be regularly checked and procedures modified accordingly in the light of any lessons learned. The effectiveness of the recall procedure can be tested by conducting a dummy recall of a particular product. This involves identifying a batch and then conducting a paper recall only to test out the systems. Such dummy recalls should be undertaken not only in normal office hours but also at the weekend and in the middle of the night. As goods are returned, they must be stored in secure storage away from all other goods until their fate is decided. Remaining stock of the suspect batch in the warehouse should also be moved into this secure storage. This is very important because there must be no risk of confusion with other batches that are good.

Recalls Effectiveness of procedures checked Test effectiveness from time to time Secure segregated storage of returned goods Essential to keep returned goods away from other goods As the recall progresses in accordance with the written procedure, written progress reports must be kept showing that all stages of the recall procedure have been adhered to. A reconciliation must also be prepared, showing the total product quantity distributed and the total quantity returned, by batch. It should identify any areas where reconciliation has not been achieved and offer reasons why. A final report must be issued to cover all aspects of the recalls including lessons to be learnt for the future conduct of such recalls. The effectiveness of SOP must also be regularly checked and procedures modified accordingly in the light of any lessons learned. The effectiveness of the recall procedure can be tested by conducting a dummy recall of a particular product. This involves identifying a batch and then conducting a paper recall only to test out the systems. Such dummy recalls should be undertaken not only in normal office hours but also at the weekend and in the middle of the night. As goods are returned, they must be stored in secure storage away from all other goods until their fate is decided. Remaining stock of the suspect batch in the warehouse should also be moved into this secure storage. This is very important because there must be no risk of confusion with other batches that are good.

End of Complaints and Recalls Do you have any complaint?

Basic Principles of GMP 6. Self-Inspection This session deals with the topic of self-inspections. The session is a quarter-day module, with approximately 30 minutes of presentation, followed by 45 minutes of group discussion and 30 minutes of feedback. Test is 10 minutes and 20 minutes for discussion

What is it? The manufacturer itself organises regular on-the-spot checks whether the GMP rules are complied with „Own” team or hired experts Report on deficiencies to the Management

Self-inspection Narrower meaning: Self-GMP inspection of own production and QC Broader meaning: also Quality audit of our own quality system Suppyers’ audit

Self-Inspection Aim Ensures that a company’s operations remain compliant with GMP Assists in ensuring continuous quality improvement The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions.

Self-Inspection Principle, 1 Should cover all aspects of production and quality control be designed to detect shortcomings in the implementation of GMP The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions.

Self-Inspection Principle, 2 Must recommend corrective action if shortcomings are observed set a timetable for corrective action to be completed The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions.

Self-Inspection Principle, 3 Special occasions may demand additional self-inspections. For example Recalls Repeated rejections by QC GMP inspections announced by the National Drug Regulatory Authority Self-inspections should be performed routinely, and may, in addition, be performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection of the health authorities is announced.

Self-Inspection Principle, 4 Team consist of personnel who can evaluate the situation objectively No conflict of interest No revenge in mind Should have experience as observers of a self-inspection team before becoming team member Lead self-inspector with experience as team member The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively; all recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up programme. It can also be a good training exercise to involve operators in the process. It is also possible to bring in people from other parts of the company, or even outside the company, if it will add value to the process.

Self-Inspection types 1. Self-inspection - informal (daily) Immediate Correction 2. Self-inspection - formal (quarterly) Improve systems 3. QC - Internal Confirm compliance (half yearly) The informal self-inspection that takes place on a daily basis is carried out by operators and managers. If something is seen to be wrong, it is immediately put right. Next is the formal self-inspection process that takes place on a regular basis. The purpose of this is to take a step back from the day-to-day activities to review for compliance to GMP and to look for ways in which the system can be improved. There may also be a need to conduct self-inspections as a result of a specific problem such as frequent rejections. This is the process we are looking at in this module. The next stage may or may not take place, depending on the size of the organization. It involves the use of QC staff as “internal auditors” to review the system for compliance. (In a smaller company, this step and the previous one may blend into one).

Scope of Self-Inspection Programme - I Written instructions Covering all aspects of GMP: personnel premises including personnel facilities maintenance of buildings and equipment storage of starting materials and finished products equipment production and in-process controls quality control There should be written instructions for self-inspection detailing what is to be inspected and at what frequency. It should be used to ensure that a consistent approach is achieved. The areas to be inspected will include (but will not be limited to): personnel premises including personnel facilities maintenance of buildings and equipment storage of starting materials and finished products equipment production and in-process controls quality control

Scope of Self-Inspection Programme - II - documentation sanitation and hygiene validation and revalidation programmes calibration of instruments or measurement systems recall procedures documentation sanitation and hygiene validation and revalidation programmes calibration of instruments or measurement systems recall procedures complaints management labels control results of previous self-inspections and any corrective steps taken In other words, a complete review of all aspects of GMP.

Scope of Self-Inspection Programme - III complaints management labels control results of previous self-inspections and any corrective steps taken documentation sanitation and hygiene validation and revalidation programmes calibration of instruments or measurement systems recall procedures complaints management labels control results of previous self-inspections and any corrective steps taken In other words, a complete review of all aspects of GMP.

The Self-Inspection Team, 1 Team leader needs: authority experience may be appointed from inside or outside the company 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 Self-Inspection Team, 2 Team members, including: local staff who are familiar with the area experts in their own field familiar with GMP may be appointed from inside or outside the company 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.

Carrying Out a Self-Inspection Frequency May depend on company requirements and the size of the company Report: results evaluation conclusions recommended corrective measures, if applicable Follow-up action Company management must evaluate both the report and corrective actions 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. 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.

Self-Inspection Quality Audit GMP Inspectors should encourage Quality Audits Useful to supplement self-inspection programme but not mandatory Examination of all or part of quality system with specific aim of improving it Usually conducted by outside experts or team appointed by management May extend to suppliers and contractors It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors.

Self-Inspection Suppliers’ audits, 1 QC department should have responsibility together with other relevant departments for approving suppliers Ensures suppliers can reliably supply materials that meet established specifications The quality control department should have responsibility, together with other relevant departments for approving suppliers who can reliably supply starting and packaging materials that meet established specifications. Before suppliers are approved and included in the specifications, they should be evaluated. The evaluation should take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it should determine the supplier’s ability to confirm with GMP standards for active pharmaceutical ingredients. Cross reference can be made to the Module for Active Pharmaceutical Ingredients.

Self-Inspection Suppliers’ audits, 1 Avoids trying to test in quality to goods received from dubious sources Before suppliers are approved they should be evaluated Evaluation does not necessarily mean an audit Should take into account the supplier’s history and nature of materials to be supplied The quality control department should have responsibility, together with other relevant departments for approving suppliers who can reliably supply starting and packaging materials that meet established specifications. Before suppliers are approved and included in the specifications, they should be evaluated. The evaluation should take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it should determine the supplier’s ability to confirm with GMP standards for active pharmaceutical ingredients. Cross reference can be made to the Module for Active Pharmaceutical Ingredients.

Auditing the Self-Inspection Programme - I Check self-inspection programme at end of formal government GMP inspection, not at beginning. GMP inspectors should assess: the SOP programmes checklists or “aide memoirs” It is advisable to check the self-inspection programme at the end of a formal government GMP inspection, not at the beginning. If your own inspection is properly formalised and systematic you won’t need to look at their own non-conformities because you will have noted them all already

Auditing the Self-Inspection Programme - II The SOP should describe teams, process, and frequency of self inspection Company policy may not permit GMP inspector to see actual deficiency reports and corrective actions The SOP should describe the teams, process, and the frequency of self inspection. Check that there is a formal program. Typically it should cover at least the next year’s activities. Company policy may not permit the GMP inspector to see the actual deficiency reports and corrective actions. Don’t fight this unless you have very good reasons to do so eg if investigating an injury or death as a result of a GMP breakdown. GMP Inspectors should be looking for compliance with the self-inspection SOP and not necessarily at the actual deficiencies recorded. Seek objective evidence of reports and action, even if these are “purged”, and audit team composition, frequency and areas covered.

Auditing the Self-Inspection Programme - III GMP Inspectors should be looking for compliance with the self-inspection SOP - not necessarily at actual deficiencies recorded Seek objective evidence of reports and action The SOP should describe the teams, process, and the frequency of self inspection. Check that there is a formal program. Typically it should cover at least the next year’s activities. Company policy may not permit the GMP inspector to see the actual deficiency reports and corrective actions. Don’t fight this unless you have very good reasons to do so eg if investigating an injury or death as a result of a GMP breakdown. GMP Inspectors should be looking for compliance with the self-inspection SOP and not necessarily at the actual deficiencies recorded. Seek objective evidence of reports and action, even if these are “purged”, and audit team composition, frequency and areas covered.

Auditing the Self-Inspection Programme - IV Ensure company is not just doing housekeeping or safety audits Check there are “Vertical” as well as normal “Horizontal” audits; both play valuable role in self-inspection Check if there is “Vertical” as well as normal “Horizontal” audits; both play a valuable role in self-inspection A “horizontal” audit is the room to room to room approach, a “vertical” audit will start with eg a batch number of a released product and then determine traceability, to training records of the people who made and tested it, to raw materials, to retention samples, to stability testing, to product registration details, etc.

End of Self-inspection

5. Contract Production and Analysis Basic Principles of GMP 5. Contract Production and Analysis This session deals with contract production and analysis. It is a half-day session, split into activities as follows: Presentation 30 minutes Group session 60 minutes Plenary feedback 30 minutes Test paper 30 minutes The global industry is changing its shape through rationalization, mergers and acquisitions. Companies are increasingly considering the use of other manufacturers to produce or manufacture their products. Companies are also finding that they do not have the technology or expertise to manufacture certain new special dosage forms. In some cases, financial targets mean that companies are not using manufacturing as a core business process. This means that the importance of contract manufacturing and testing of products is also increasing. It may also mean that companies no longer have the technical expertise in-house to fulfil all the requirements for GMP. Increasingly many companies in developing countries are used as contract accepters. It is essential for everyone concerned to understand the principles involved and the detailed mechanisms required for managing contract work properly.

Contract Production and Analysis Principle Contract production and analysis must: Be correctly defined, agreed, controlled in order to avoid misunderstandings that could result in inferior product Have a written contract clearly establishing each parties’ duties which ... Clearly state how the authorized person when exercising his or her full responsibility releases each batch or issues certificate of analysis The main principle underlying contract production and analysis is very simple. The work has to be clearly defined, agreed and controlled to avoid misunderstandings. If misunderstandings arise, then work may be done which does not meet the quality standards set. The simplest way to avoid such misunderstandings is to have a written contract, setting out the duties of all parties to the contract and the standards that must be met. The standards of performance refer not only to product quality standards but also many other non-GMP aspects, e.g. relating to financial matters. It must be clear to everyone who is the authorized person, having the responsibility and the final authority to release a batch for sale. The authorized person must be involved in setting up the contract and agree to the way in which information will be provided that will allow him/her to make a decision to release a batch of product.

Contract Production and Analysis General Issues All arrangements must be in compliance with marketing authorization Written contract must cover manufacture, analysis and any technical arrangements Should allow audit of contract acceptor In case of contract analysis, the authorized person must still give final release for sale First of all let’s look at the general issues that become apparent when companies start contract work. The contract giver must ensure that the contract accepter has a valid licence to manufacture the product under contract. Information about any contract manufacturer or analysis must be included in the application for marketing authorization, and changes approved by the national authority before implementation. If product manufacture is transferred from its existing location to a new contract location, then it is likely that the equipment used will be different to that appearing in the product registration file. Such a change of manufacturing process or condition may need the approval from the quality control department and the national regulatory authority before implementation. A written contract should be drawn up that specifies all the technical details of the work to be done and the standards to which the work must conform. The people who prepare the section of the contract that sets out these technical details must be -technically qualified to do so. The contract giver must be given the right to audit the premises of the contract accepter. This is to assess compliance with GMP and to reassure it that the premises and equipment will provide a product that meets the requirements of the marketing authorization. It will also permit the contract giver to identify those areas where it may be able to contribute practical product knowledge to the staff of the contract accepter. In the case of contract analysis, the product must only be released for sale by the person authorized to do so. This must be clearly specified in the contract. Countries’ national laws may modify exactly how this is applied.

Contract Production and Analysis Responsibilities of the Contract Giver, 1 Must assess competence and compliance of contract accepter with GMP (cont’d) Let us now look in more detail at the responsibilities of the contract giver. First of all, the contract giver is responsible for assessing the competence of proposed contract accepters that they will be able to do the work. The contract giver will normally know the product better than anyone else. This will be the case if the contract giver has developed the product. It knows the work that needs to be done. It must assess whether the companies that offer to do the work really have the capability to do it. This evaluation must also include an assessment as to whether they are able to operate in accordance with the GMP principles described in the WHO GMP text. Once the conclusion has been reached that the contract accepter has not only the technical competence but also the GMP competence, then the contract giver must provide a full package of technical information to the contract accepter. This should enable the contract accepter to make the product safely and in accordance with the marketing authorization. This means that all the information relevant to personnel, premises and equipment must be provided. If there are hazards associated with cross-contamination of other products these must be highlighted. Finally, the product made or tested under the contract must only be released by the authorized person in compliance with the marketing authorization. In some cases the authorized person may be a designated staff member of the contract accepter if this responsibility is delegated in writing by the contract giver and if such delegation is permitted by national regulations.

Contract Production and Analysis Responsibilities of the Contract Giver, 2 All necessary information must be provided to the contract accepter in order to: have the operations carried out correctly in accordance with the manufacturing authorisation and other legal requirements be fully aware of any problems with the product, work, tests that might pose a hazard to premises, equipment, personnel, other materials or other products Let us now look in more detail at the responsibilities of the contract giver. First of all, the contract giver is responsible for assessing the competence of proposed contract accepters that they will be able to do the work. The contract giver will normally know the product better than anyone else. This will be the case if the contract giver has developed the product. It knows the work that needs to be done. It must assess whether the companies that offer to do the work really have the capability to do it. This evaluation must also include an assessment as to whether they are able to operate in accordance with the GMP principles described in the WHO GMP text. Once the conclusion has been reached that the contract accepter has not only the technical competence but also the GMP competence, then the contract giver must provide a full package of technical information to the contract accepter. This should enable the contract accepter to make the product safely and in accordance with the marketing authorization. This means that all the information relevant to personnel, premises and equipment must be provided. If there are hazards associated with cross-contamination of other products these must be highlighted. Finally, the product made or tested under the contract must only be released by the authorized person in compliance with the marketing authorization. In some cases the authorized person may be a designated staff member of the contract accepter if this responsibility is delegated in writing by the contract giver and if such delegation is permitted by national regulations.

Contract Production and Analysis Responsibilities of the Contract Giver, 3 Authorized person (must be at the Giver!) Batch release in compliance with specifications Let us now look in more detail at the responsibilities of the contract giver. First of all, the contract giver is responsible for assessing the competence of proposed contract accepters that they will be able to do the work. The contract giver will normally know the product better than anyone else. This will be the case if the contract giver has developed the product. It knows the work that needs to be done. It must assess whether the companies that offer to do the work really have the capability to do it. This evaluation must also include an assessment as to whether they are able to operate in accordance with the GMP principles described in the WHO GMP text. Once the conclusion has been reached that the contract accepter has not only the technical competence but also the GMP competence, then the contract giver must provide a full package of technical information to the contract accepter. This should enable the contract accepter to make the product safely and in accordance with the marketing authorization. This means that all the information relevant to personnel, premises and equipment must be provided. If there are hazards associated with cross-contamination of other products these must be highlighted. Finally, the product made or tested under the contract must only be released by the authorized person in compliance with the marketing authorization. In some cases the authorized person may be a designated staff member of the contract accepter if this responsibility is delegated in writing by the contract giver and if such delegation is permitted by national regulations.

Contract Production and Analysis Responsibilities of the Contract Accepter, 1 Competence must have the necessary facilities, premises and equipment, both in type and in quantity, to undertake the work. must have a manufacturing authorization to do this type of work. its staff must have the necessary qualifications, training and experience to be able to do the work The contract accepter also has responsibilities. The company must be competent to do the work. It means that it has the necessary facilities, premises and equipment, both in type and in quantity, to undertake the work. It must have a manufacturing authorization to do this type of work. This means that its staff has the necessary qualifications, training and experience to be able to do the work

Contract Production and Analysis Responsibilities of the Contract Accepter, 2 No subcontracting without approval to accept a 3rd party, contract giver must be able to undertake audits needed to be reassured that the 3rd party is competent. All the responsibilities placed upon the contract accepter must be fulfilled by any third party contractor that may be employed No conflicting activities The contract accepter may not pass the work or any part of it on to a (third) subcontractor party without the approval of the contract giver. In order for the contract giver to be able to accept a third party, it must be able to undertake all the audits that it needs to be reassured that the third party is competent. All the responsibilities placed upon the contract accepter must be fulfilled by any third party contractor that may be employed. Finally, once a contract accepter has signed the contract, it must not then undertake new work which might adversely affect the quality of the existing products. An illustration of this would be to take on manufacture a penicillin product in the same facility, as other products of the contract giver.

Contract Production and Analysis The Contract, 1 Each party’s responsibilities defined Technical aspects drawn up by competent persons Batch release mechanisms; by the authorized person The contract that is prepared between the contract giver and the contract accepter must identify clearly the responsibilities each has with respect to the relevant sections, and the work to be done. All the technical details and specifications must be prepared by competent technical staff. All the arrangements must be in accordance with the marketing authorizations and agreed by both giver and accepter. The contract must be very clear about the way in which the authorized person will approve the product for sale. It must enable the authorized person to check that each batch has been made in compliance with the marketing authorization. The contract must specify who is responsible for the purchase and testing of all incoming materials and their release to production. It must also specify all the in-process testing that is to be done and who is responsible for sampling and analysis. In the case of contract analysis, the contract should specify whether the contract accepter is responsible for sampling, and if so where the sampling is to be done. If contract analysis is being undertaken then the contract must show how the information will be processed and in what time span it will be done.

Contract Production and Analysis The Contract, 2 Materials purchasing, testing and releasing Production and in-process QC (IPQC) and QC Sampling and analysis; who takes the sample? and where? The contract that is prepared between the contract giver and the contract accepter must identify clearly the responsibilities each has with respect to the relevant sections, and the work to be done. All the technical details and specifications must be prepared by competent technical staff. All the arrangements must be in accordance with the marketing authorizations and agreed by both giver and accepter. The contract must be very clear about the way in which the authorized person will approve the product for sale. It must enable the authorized person to check that each batch has been made in compliance with the marketing authorization. The contract must specify who is responsible for the purchase and testing of all incoming materials and their release to production. It must also specify all the in-process testing that is to be done and who is responsible for sampling and analysis. In the case of contract analysis, the contract should specify whether the contract accepter is responsible for sampling, and if so where the sampling is to be done. If contract analysis is being undertaken then the contract must show how the information will be processed and in what time span it will be done.

Contract Production and Analysis The Contract, 3 Reference standards and retention samples who keeps them? where and under what conditions are they stored? Records: manufacturing analysis distribution should be kept by or made available to the contract giver All manufacturing, analytical and distribution records and reference standards or retention samples must be kept by or be made available to the contract giver. Any records relevant to assessing the quality of a product in the event of a complaint or a suspected defect must be accessible to the contract giver. These records must also be specified in the defect/recall handling procedures used by the contract giver. This is to ensure that in the event of the need to recall a product, the contract giver can immediately access necessary records. The contract should also specify clearly what would happen to materials that are rejected.

Contract Production and Analysis The Contract, 4 Rejection management needs to be described for: starting materials intermediate and bulk product finished product = What would happen to materials that are rejected! All manufacturing, analytical and distribution records and reference standards or retention samples must be kept by or be made available to the contract giver. Any records relevant to assessing the quality of a product in the event of a complaint or a suspected defect must be accessible to the contract giver. These records must also be specified in the defect/recall handling procedures used by the contract giver. This is to ensure that in the event of the need to recall a product, the contract giver can immediately access necessary records. The contract should also specify clearly what would happen to materials that are rejected.

End of Contract Production and Analysis

Exam topics

Complaints and recalls in GMP Principles of complaint handling What to do and to record? Which are the possible decisions? Defect classification (3) How to perform recalls and why? Why distribution records are essential?

Self-inspection in GMP Meanings Aims, principles Types Scope The Self Inspection Team Speak about the different audits

Contract production and analysis in GMP Define them. Why they may be needed? Tasks of the Contract Giver Tasks of the Contract Accepter What kind of expertise is needed to formulate a manufacturing contract? Batch release responsibility Subcontracting rules