GMP Inspection Process

GMP Inspection Process
World Health Organization 24 November, 2018 The Inspection Having looked at the types of inspections, the role of the inspector and how to prepare for an inspection, we now move into the topic of how to carry out the inspection. This module is split into three sessions of roughly two hours each. Each session will follow the standard pattern of 30 minutes presentation, 45–60 minutes group discussion and 30 minutes feedback.

World Health Organization
The Inspection World Health Organization 24 November, 2018 Objectives 1. To discuss the process of conducting an inspection 2. To review a number of inspection techniques 3. To discuss issues you may encounter when performing an inspection The three objectives of this module are: To discuss the process of conducting an inspection; To review a number of inspection techniques; To discuss issues you may encounter when performing an inspection.

The Inspection World Health Organization 24 November, 2018 Timetable Entry briefing/opening meeting Orientation tour Fact finding and assessment Review progress against audit plan Revised activity Final review/recommendations Exit review with management/closing meeting Report with time frame As we discussed in the module on preparation, there should be a programme for the inspection and this should include a draft timetable. While every visit will be different in the detail, there will be some standard approaches: All visits should start with an entry briefing meeting (opening meeting) to ensure that the objectives of the visit are explained and understood. Arrangements should have been made to provide any help you may need for the inspection, including the provision of technical persons to accompany you during your visit if required, in accordance with local regulatory authority practice. It is useful to have an orientation tour of the plant, particularly if it is the first time that you have visited it. Remember that this is an initial walk-through only – do not be pulled into detailed discussions at this point. Then it is time to start the main activity of the inspection – the fact-finding approach to assess compliance with GMP. At some point in the inspection, it will be necessary to review the programme and see whether it needs to be revised in the light of the information that has been obtained to far, and the progress made. (For a review of two or more days, this will be necessary at the end of each day). The inspection then continues using the revised plan. Make sure that the persons involved in the inspection are aware of any changes, so that they can amend their plans accordingly. There needs to be some time at the end of the visit for you to review your findings. This is particularly so when you are inspecting as a team of two or more, each inspector visiting different parts of the site at the same time. Decide what you will report on during the exit meeting. The last activity at the company is an exit meeting with the management team. To tie it all together, the inspection report is issued to the company with recommendations for action.

The Inspection World Health Organization 24 November, 2018 Getting Started Location Contact Time Introductions Walk-round Company escort An inspection visit only lasts for a certain length of time and it is important that you get as much out of it as possible. Here are a few recommendations for making sure that everything goes according to plan and the inspection starts promptly. For announced inspections, agree in advance the time that you will arrive. Make sure you know the exact location of the company and how to get there. Get there in good time. Remember who the contact persons are. An inspection usually begins with a meeting between the inspectors, representatives of the company or plant management and those responsible for the areas to be inspected. The inspectors should introduce and identify themselves and present their credentials. Explain the purpose of the inspection. As we discussed earlier, you may wish to do a quick walk-through of the facility to get orientated with the design and lay-out of the facility. The company usually appoints at least one escort for the inspector(s). These escorts should know the quality system and be involved in self-inspection programme of the company. Try to start the inspection or plant tour as soon as possible after arrival.

The Inspection World Health Organization 24 November, 2018 Remember that an Inspection…. Is a systematic approach Involves interpersonal skills Identifies deficiencies Looks at what went wrong Requires participation from both parties There are number of things that you need to remember about an inspection: First of all, inspection is a systematic approach. As you will be assessing compliance with GMP guidelines, it is recommended that you have a systematic approach to assist you in remembering all the aspects that need to be assessed. You need to have good interpersonal skills in order to get the best out of the people you are talking to. An inspection should identify deficiencies … and that means looking at what is wrong,or what went wrong. An inspection requires participation from both parties – there isn’t much point in asking lots of questions if they are not going to be answered. You must also listen to the answers and evaluate them carefully. There is no point in asking a question and then not listening to the response. Frequently, the response will lead to the next question. Expect the company to know more about its equipment, facilities and processes than you do. Ask relevant questions in all the areas about the processes, procedures, systems and equipment.

The Inspection World Health Organization 24 November, 2018 Methods of Fact-Finding Trace forward Trace backward Random There are three main methods for fact-finding that an inspector can use in an inspection. To “trace forward” is the method followed, by starting the inspection with the receiving of starting materials and then following the production flow through the factory to the dispatch warehouse at the end. This will tend to be a general exercise that concentrates on the physical systems and is normally followed by most inspectors. To “trace backward” is the method where you review the history of a specific batch of a product through the process and system. This will be a fact-based exercise that concentrates on the processes, procedures and activities of that specific batch of product. The “random” approach is where you start from points around the factory that appear to be significant. You will then inspect any area at random and will not necessarily follow the logical flow of material or manufacturing process. This approach is to be discouraged for an inexperienced inspector. The choice of method is based on a combination of the purpose of the inspection and the previous history of the company with regard to inspections with the personal choice of the inspector.

The Inspection World Health Organization 24 November, 2018 Asking Questions….. Open questions starting with: What Why When How Where Who Silence can be very powerful Although you will be able to get some of the information you need from your own observations and from documents, much of it will come from the questions that you ask. It is important to ask “open” questions that result in information being given in the answer. Refrain from asking “closed” questions that can be answered with "yes" or "no”. Examples of “open” questions are: Could you describe what happens then? Why do you do that? When is this carried out? How do you do that? Where is that done? Who is responsible for doing it? Finally, if you feel that there is more information that needs to come out — try silence. Silence can be very powerful and it makes people uncomfortable. People often tend to try to find something to fill it.

The Inspection World Health Organization 24 November, 2018 Good Listening – I Stop talking! Help the speaker to feel free to talk Be approachable Show the speaker that you are interested Remove distractions Try to understand the speaker’s point of view We have talked about asking questions, but we must remember that the purpose of those questions is to get information. You must therefor be a good listener. We are now going to look at a few rules of good listening: Stop talking. Ask the question, then wait for an answer. If you try to do all the talking, the other person will allow you – but you won’t get the information you need. Help the speaker to feel free to talk. Be open to the responses and try to appear approachable. Show the speaker that you are interested. Look at them, nod, and smile. Do not ask the question and then loose interest, or look around you at everything else whilst the answer is being given. Remove distractions. If the questions are detailed or likely to take time, then try to go somewhere quiet where you can both concentrate on what is being said. (Trainer can offer examples of distractions). Try to understand the speaker’s point of view. Even if you disagree with the answer, make sure that you understand why it has been given and the background to it. Remember to assess what the impact could have been on the quality of the product.

The Inspection World Health Organization 24 November, 2018 Good Listening – II Be patient Hold your temper Try not to criticize Ask questions Stop, look and listen Be patient. Remember that the person may not be used to answering questions (particularly if it is a shop-floor operator) and may need time to frame the answers. Do not rush the operator for an answer. Hold your temper. Do not get cross, whatever the provocation. You need to remain calm at all times in order to get all the information that is available. It could happen that the company personnel want to argue issues - do not loose your temper. Try not to say things that can be taken as a personal criticism by the person you are talking to. Make sure you address the issue (what went wrong) and not blame or appear to blame the person. Keep on asking relevant questions. If the first answer does not give you all the information you need, then ask supplementary ones. It is important to realise, that you have to stop, look and listen. It is important to be observant– take time to look around. If you just ask questions from area to area, and try to move through the manufacturing areas, you will not see how operators work, how they perform in process controls, or handle materials and products. This is critical in assessing compliance with GMP.

The Inspection World Health Organization 24 November, 2018 Group Session 1 You will be given a situation about which you have to determine the factual information regarding the situation. The people being inspected will be truthful, but will not volunteer any extra information List up to 5 questions that you would ask in order to obtain the information that you require We will now have our first group discussion. Each group will be given a situation that you could be faced with during an inspection. You need to work out what questions you would ask in order to get the information you need. To make it close to real life, we have said that the people being inspected will be truthful in their answers (and in most inspections, you will find that this is so). However, they will not volunteer information that you do not ask for. (Trainers will need to develop appropriate situations, based on the prior knowledge and experience of the trainees. Possible issues: Establish whether raw materials are sampled and tested in accordance with the specifications and SOPs, establish whether proper training is given to employees in production and quality control, establish whether validation had been performed on the HVAC system. Following the feedback session on these group discussions, move on to the next presentation.)

The Inspection World Health Organization 24 November, 2018 How to Take Notes Detail and facts — trust, but verify Specifics not generalizations Record detail as seen Ensure accuracy Be open In the second part of this module, we shall be looking at how you should report your findings after the inspection. One of the important skills needed for a successful inspection is that of taking notes. There is nothing worse than walking away from a discussion and finding that you have forgotten to record the important points. In many cases, you will be inspecting on your own and will need to ask questions, evaluate the answers, observe the facts and take notes. So first of all, let us look at some ways on how to take notes: Detail and facts – You need to concentrate on obtaining relevant facts at a detailed level. Note specifics such as room numbers, equipment numbers, document numbers, batch numbers, names etc.It is important that you verify the responses given to your questions as facts, no matter how much you trust the person giving you the information. If the operator says that he has cleaned the mixing vessel and recorded the information in a record, look at the record and verify this. You should never make assumptions and never be satisfied with assurances. Record specific information, not general impressions, e.g. ampicillin 250 mg capsules, batch number X123 was stored in bulk store number 3 where there is no temperature control, monitoring or recording. (Do not just note ampicillin capsules were stored in a bulk store where the temperature is not monitored). Record the detail as you saw it. You need a record of what you see, not what you are told that you should see. If the area is dirty and there is a lot of dust evident, record it as such, even if they say that is isn’t really dust because they had just cleaned the area. Ensure accuracy – inaccurate statements and observations undermine credibility and authority of the inspector if you are proved wrong in your facts (particularly with senior management). Be open – The results of your inspection will be the subject of a report after you have left, so there is nothing to be gained by hiding what you are recording.

The Inspection World Health Organization 24 November, 2018 What to Record – I Persons interviewed Document numbers Equipment numbers Item identification There are a few specific things that you need to record wherever they are appropriate: The persons being interviewed – their names and job titles and/or responsibilities. (You may also want to evaluate the SOP for training and training records of personnel. It will he helpful if you have recorded names of operators during the inspection, when you assess training records later. You can then verify that an operator had been receiving continued training). The reference number of any document that is reviewed – both the issue number and specific batch number if applicable (e.g. SOP numbers). The reference number of any equipment that you are looking at and that will be the subject of a comment in your report. You could also select a piece or pieces of equipment to evaluate compliance with the planned preventative maintenance program later during the inspection. Any other relevant reference numbers, for example room numbers or instrument codes should be recorded.

The Inspection World Health Organization 24 November, 2018 What to Record – II Selection of document recipients Condition of environment Changes to facilities, equipment, etc. Layout of area Any obvious non-conformities If you are reviewing documentation, it is useful to record some of the names of the recipients. Then you can discuss the same documents from their point of view when you meet with them. An example is the SOP for sampling. You could discuss the SOP with the sampler when assessing the sampling process. You should also scrutinise the documentation such as master formulae, specifications and batch records. The condition of the environment is critical – not just temperature and humidity but also general housekeeping. Assess and record findings such as the presence of dust in manufacturing areas, paint flaking, holes in walls, floors or ceilings, and so on. Make sure these aspects are controlled, monitored and recorded in compliance with a written SOP. Significant changes in facilities, equipment products and senior personnel since the last inspection should be noted. Changes represent possible areas of weakness, for example changes in equipment could result in changes to the manufacturing method, validation and training. It is useful to record the layout of the building or factory. You may have been provided with drawings by the company, but you might need to make detailed sketches in some cases to illustrate your notes. It will also be of help when you write your report, to remind you of the specifics of the areas inspected. An inspection will cover not just the main production areas but also goods receipt, warehousing, laboratories, utilities areas and workshops. Any obvious non-conformity should be recorded even if it is put right straight away and will not be mentioned in the final report. The number of such instances during your inspection will give an overall view of the way that GMP is being complied with - or do they quickly correct aspects during the inspection as a means of trying to comply.

The Inspection World Health Organization 24 November, 2018 How to Record – I Checklists Flowcharts/process charts Symbols such as a star (*) or a tick Checks and follow-up There are a number of ways in which records and notes can be made during the inspection. The one that you choose will depend on what is most appropriate at the time, the inspectorate policy and your personal choice. The following are just some suggestions from personal experience: Checklists are a detailed, but structured way of taking notes. We will look at these in more detail in a few moments. Flow-charts can be a good way of making sure that you understand an operation and how it fits into the overall system. The flow-chart approach can also be useful for understanding the process of manufacturing itself. Use of symbols may make your notes easier to interpret when they are read back. For example, you could make use of a square drawn round items for the report; or a star to indicate items for follow-up and checking at a later stage during the inspection. Each inspector has his/her own way of making sure that everything asked for during the inspection is shown, or presented or followed up before the end of the inspection. These observations can be recorded on a separate page (marked “checks”) or the observations can be marked with an asterisk on the far right of the page. These can then be ticked off when followed up or presented. Which ever system you use, make sire that documents, results and other things asked for during the inspection, are presented to you before you finalise the inspection. If these are not presented to you, they may not exist, or the company had forgotten to show them to you. However, you can not assume, and can then not report on the matters.

The Inspection World Health Organization 24 November, 2018 How to Record – II Highlights Short notes for the report (reminders) Tape recorder Video camera Camera Another useful approach is to record everything as it is given, and then to review the notes afterwards. You can then use a highlighter pen to emphasize the key points. This helps to organize the notes for later report preparation. Some people prefer to think about their notes later, and just make short notes at the time of the inspection, for writing up later in the report. This method relies on a good memory and the time to write up the same day whilst the facts are still fresh in your memory. A tape recorder is also used by some inspectors. However, this may be off-putting for those being interviewed as it makes some operators nervous. The inspector could also seem to be more remote. A video camera is useful for recording information about the plant and premises, but will be of little use in obtaining information, as it will prevent people from relaxing and answering questions sensibly. A still camera may also be useful for taking photos of areas, equipment or storage of materials. It should be noted that you may need to obtain permission from the company before using a tape recorder or still or video cameras, unless national legislation provides the inspector with the authority to use such equipment.

The Inspection World Health Organization 24 November, 2018 Checklists Are structured Detailed Standard for all full inspections Advantages Useful as reference Good for training inspectors Disadvantages Can lead to overlooking vulnerable areas of QA Some inspectorate prefer to do inspections by using checklists. Checklists are comprehensive lists of all the detail GMP requirements and guidelines that a company should be expected to follow and comply with. They should be drawn up from the GMP text that is in use in the country. Because they are comprehensive, they will frequently be many pages in length. Depending on local circumstance, they may form the basis of the report of an inspection of a factory. If it is the policy of the inspectorate to use checklists, then these should be used as standard practice for all full inspections to ensure that the inspectors follow the same principles. Checklists have a number of advantages and disadvantages. Advantages: They are comprehensive documents, and all the questions have been thought about in advance. They can be very useful as a reference document, and are certainly good to use as an aid to preparation. They are useful for the training of inspectors They are based on the key standards, and most importantly, they already exist. Against their favour: They are very structured and do not allow room for the individual issues that will relate to a particular facility. They are not practical to use in an interview situation. You could end up in an exercise of ticking the boxes. For an experience inspector, knowledge of the manufacturer’s weak points coupled with intuition may serve better than checklists.

The Inspection World Health Organization 24 November, 2018 Checklists – How to Use Them Follow, but be prepared to be flexible Use in preparation stage Use to collect information and chart progress Preparation for the exit meeting Preparation of the report In summary, it can be said that checklists have their uses in certain situations, but not in others. Keep the following aspects in mind, should you decide to use checklists. This may assist you in using them effectively: First of all, do not allow them to dictate the way that an inspection proceeds. Be prepared to be flexible and go beyond the scope of the checklist where necessary. Use them to help you in your preparation for the inspection. Use them to record the information you collect during the inspection, review your notes and chart progress during the inspection. Use them in preparation for the briefing during the exit meeting Use then to write the report after the inspection.

The Inspection World Health Organization 24 November, 2018 Aide-Memoire Simple, short list of actions and aspects to be checked Tailored for the inspection Checklist and/or an aide-memoire We discussed the aide-mémoire briefly earlier in this module. What is an aide-mémoire? Aide memoire could be defined as an “aid to your memory” or a document to remind you to do or check certain aspects during the inspection. It is thus an abbreviated list of specific actions that you wish to work on during this inspection. This list is prepared during the preparation phase of the inspection where you will list specific aspects that you want to evaluate during the inspection. It will be individually tailored to suit the specific inspection. It will probably be not more than 1-2 pages long. Inspectors can work with a checklist and/or an aide-mémoire depending on the type of inspection to be done and the national policy

The Inspection World Health Organization 24 November, 2018 Taking Samples Finished-released products Raw materials In-process materials Inspector or sampler Number of samples and sample size Authorization It is normal practice for the inspector to be able to take samples during an inspection for testing purposes by the official quality control laboratory. (Samples do not have to be taken during every inspection). Samples are usually taken from released products but may also be taken from stocks of raw materials or in-process materials. It is preferred that the samples be collected by the inspector in the presence of the company’s escort. If the company wants to sample the product or material, then it should be done under the supervision of the inspector. When collecting samples care should be taken to protect sample integrity. There should be a written procedure for sample collection, analysis and documentation. The following should be considered when developing the procedures and a standard format for sampling: name(s) of the sample product(s), batch(s) numbers(s), date, source number of sample, and remarks on type of packaging and storage conditions; circumstances of sampling, e.g. suspect quality defects, routine surveillance, verification compliance with GMP; instructions for the placing of seals on containers of sample materials; written confirmation of authorisation for the receipt of the samples by the inspector. Adequate quantities should be collected from the same batch(s) and divided into three equal portions. One portion should be kept in a sealed container which is signed by the inspector and the responsible person of the company and kept in the custody of the company to serve as reference in case of controversy. The second portion should be given to the company’s “escort” for “in-house” testing. The third portion should be taken by the inspector for testing by the official quality control laboratory.

The Inspection World Health Organization 24 November, 2018 Objectives of Exit Meeting Communicate observations Inform management of findings No surprises in report You should always finish the inspection with an exit or closing meeting. Local procedures or legislation may modify this. This meeting is held before leaving the factory and it has two objectives: It is an opportunity for the management team to be informed of the findings of the inspection. Companies often widen the audience for these meetings to more than the immediate technical team as it can be a learning experience for personnel. It also ensures that there will be no surprises when the final report is submitted. The observations, non-compliancies and compliancies, should be reviewed and clarified during the closing meeting. You should present a summary of your observations to the company during the closing meeting. If only a summary is given, make sure that you inform them that a fulll report will be sent to the company.

The Inspection World Health Organization 24 November, 2018 Preparing for Exit Meeting – I Group non-compliances Categorize non-compliances critical, major and minor The next two slides deal with preparing for the exit meeting: Assuming that there is more than one inspector involved, the first step is to group non-compliances so that the whole team has the same set of information. The non-compliances should then be categorised into critical, major, and minor non-compliances, or a similar grading system. Depending on the number of non-compliances identified, you may not want to cover all of them in the exit meeting. In which case, it is worth ranking them in order of priority so that at least the key ones are discussed.

The Inspection World Health Organization 24 November, 2018 Preparing for Exit Meeting – II Anticipate questions and discussion or debate In the case of a team of inspectors agree on a spokesperson agree on a note-taker It is important to anticipate what questions might be raised in the meeting and have answers ready; this is particularly true for any contentious issues. Assuming there is a team of inspectors involved, the team leader will normally be the spokesperson; alternatively, the whole team may take part in the presentation, each covering his/her own areas of expertise or areas inspected. It is important that someone from the team is responsible for taking notes during the meeting.

The Inspection World Health Organization 24 November, 2018 Exit Meeting Attendees The inspectors Senior management representative Inspected managers and supervisors Other interested parties The attendees at the exit meeting will often depend on national and company culture and practice. The inspectors who participated in the inspection will obviously attend. A senior management representative is essential – often the technical director or other board member – since he/she will be responsible for agreeing any actions that incur significant investment. The managers and supervisors whose areas have been inspected should also be present (although on occasion, they will have a separate meeting with the inspectors prior to the senior management meeting). As discussed previously, the company may widen the attendees as a training exercise for other members of the management team.

The Inspection World Health Organization 24 November, 2018 Running the Meeting – I Inspectors must lead Concise presentation Discussion When to invite discussion and when to limit the discussion Mention good points before deficiencies Here are a number of tips for making the meeting as effective as possible: It is important that the inspectors lead the meeting and control the agenda so that all the pertinent points are raised. List any unsatisfactory findings and outline the irregularities and other observations. Your presentation should be made in one go, without any discussion. Should you be interrupted during the reporting session, you could indicate to the members at the meeting that the opportunity to discuss points comes later in the meeting. If at all possible, start the meeting by mentioning the good points that have been observed during the inspection. It is important that these are recognized. If you mention them up front, it will create a better atmosphere in which to review problems. Remember to thank them also for their hospitality.

The Inspection World Health Organization 24 November, 2018 Running the Meeting – II Treat challenges politely Discuss and resolve conflicts Admit if wrong Don’t back down if convinced you are right You should realise that the people whose departments are being criticized may feel vulnerable, particularly in front of senior managers. Be prepared for some challenges and deal with them calmly and politely – this should defuse the situation. Any points of contention should be discussed and resolved before the meeting ends. It is possible that there could be occasions where you have misunderstood what you have been told or made a mistake in your observations. When this does happen, admit it and agree the amended recommendation or action. However, if you are convinced that you are right, do not back down. The role of the inspector is to make observations on compliance with GMP and recommendations on improvements. Do not be intimidated by arguments that you do not agree with.

The Inspection World Health Organization 24 November, 2018 Writing the Inspection Report Each team member writes own part Team leader has overall responsibility Signed by all team members Approval from supervisor To company within 4 weeks or less If there is an inspection team, each team member writes the part that he/she has inspected and is responsible for. The team leader has the overall responsibility for the final report. He/she must remove inconsistencies between the various parts, and ensure that the sequence of the various parts is logical and the conclusions drawn are valid and founded on facts. The report is signed by all the team members. It then goes to the supervisor for approval (if required by the country policy or protocol). The timing of the report is important. If the company has to wait a long time, everyone will have moved on to other things and it will have less impact than if it is delivered promptly. A maximum delivery time should be set by the inspectorate. This could be ten days to 4 weeks maximum.

The Inspection World Health Organization 24 November, 2018 Report Content Part 1. General information on company Part 2. Description of the inspection Part 3. Observations Part 4. Conclusion and recommendation Annexes Appendix 2 of the WHO Provisional Guidelines in the Inspection of Pharmaceutical Manufacture provides an example of the type of report that can be written after an inspection. You will find a copy of this text in your handout. The report should be divided into 4 parts as shown on this slide: The first part: General information about the company can be taken directly from the information provided by the company itself, provided it is annotated as such and verified during the inspection. The second part should describe the progress of the inspection, listing all the parts of the factory,warehouse, laboratory etc that have been inspected. The third part is devoted to observations, either negative or positive, including any major changes (improvements and deterioration) that have taken place since the previous visit. Negative observations should differentiate between poor systems and failure to comply with the system. An example is lack of cleaning in a particular area. Is it due to an inadequate SOP, or lack of compliance with an SOP that covers all aspects of cleaning. Positive observations should be recorded A description of the process that is carried out particularly well and would be considered as examples of good manufacturing practice. The final part consists of the inspectors’ summary and conclusion, including corrective actions and recommendations. You could also add any supplementary documentation as annexes to the report. (It is advised that you discuss the contents of part three and four with the company during the exit meeting, where possible).

The Inspection World Health Organization 24 November, 2018 Do Not Include Subjective opinions Irrelevant information Ambiguous statements Antagonistic statements There are some aspects that should not be included in the report, although they may be discussed at the exit meeting if appropriate: Your subjective opinions as opposed to fact. Information that is not relevant to the inspection. Ambiguous statements that cannot be supported. Antagonistic statements that do not contribute to the inspection.

The Inspection World Health Organization 24 November, 2018 Style of Report Use past tense Keep it simple and based on fact Include a summary The whole inspectorate should have a consistent style for inspection reports that is used by everyone (using a standard format). Here are a few suggestions on making the report readable and effective: Use the past tense: “It was observed…” or “It was noted that…” Keep it simple and based on fact – it is not necessary to complicate the report. There is no room for opinion or ambiguities - remember the specifics that we discussed earlier when referring to documents, products or equipment. Provide a summary – covering your general impression of the company and your assessment of whether they achieve compliance with GMP. In particular, refer to specific incidents of non-compliance.

The Inspection World Health Organization 24 November, 2018 Report with Covering Letter to Company Any corrective actions to be taken Time limits for implementing them Confidential information Exchange of reports Regulatory measures if not implemented After the report has obtained supervisory approval, it should be sent with a covering letter to the company management. As said earlier, this should be done not later than 4 weeks after the inspection, earlier if possible. If the report concludes that improvements and corrective actions need to be implemented, these can be summarized in the letter or pointed out in the report. Time limits for carrying them out should be given, and the consequences of not doing so can be pointed out. (Corrective actions and time limits should have been discussed in the exit meeting, but a formal, written statement should be made when the report is sent to the company). Inspection reports are normally treated as confidential documents, depending on national legislation. However, under certain international agreements, reports are exchanged between regulatory authorities (e.g. mutual recognition agreements, memoranda of understanding or signatories to co-operation schemes).

The Inspection World Health Organization 24 November, 2018 Regulatory Measures Depend on national legislation. Examples: For new plants No manufacturing licence/GMP certificate until compliance For licence/certificate holders Warnings Fines Suspension/withdrawal of marketing authorization for product(s) Suspension/withdrawal of manufacturing licence/GMP certificate Access to appeal Countries use different strategies to ensure that legislation is enforced. The regulatory measures available to the authority in cases of non-compliance are described in the national legislation. If compliance with GMP guidelines is a legal requirement, the inspectors must know which sanctions they can impose on manufacturers who do not comply. For new manufacturing plants the issuance of a licence can be delayed. If a company is required to have a licence in order to distribute products made in the plant, this is usually sufficient to improve compliance. For licences already issued, it may be sufficient to warn that the authority may withdraw the licence. The authority may be empowered to impose fines. This measure may be used if non-compliance does not constitute a serious health risk. In some countries the authority has the legal power to suspend or withdraw the marketing authorization for a product if the manufacturer does not comply with GMP during production of that specific product. The authority could also suspend the issue of a certificate of compliance with GMP. Suspending or withdrawing the manufacturing licence and closing down a plant are strong measures that should be used when products from the plant is considered to constitute a serious hazard to health. In severe cases of non-compliance the authority may consider initiating court proceedings. The authority may need to spend substantial time and resources if they decide to do this, which should not be undertaken without careful consideration. The manufacturer should have access to appeal to a higher authority about all regulatory decisions, including sanctions for non-compliance with GMP.

The Inspection World Health Organization 24 November, 2018 Group Session 2 You will be provided with a set of observations arising from an inspection of a factory Review the observations, categorize them, prepare corrective actions and prepare for the exit meeting with the company We will now move into the second of our group sessions. Each group will be asked to prepare for an exit meeting with the management team of the company that has just been inspected. You will be of provided with a list of observations. Decide on the key issues to be discussed in the exit meeting. Develop some recommendations on corrective actions, and devise a presentation of your conclusions.

The Inspection World Health Organization 24 November, 2018 Company Strategies – I Tricks Remedies Time-wasting Threaten to extend inspection Side-tracking Stick to programme Provocation Remain calm Samples provided Select your own sample Special case Take notes and keep looking Circular argument Recognize and stop We now come to the third and last part of this module. Earlier on, it was mentioned that in most cases, people answer questions truthfully. Deliberate lying is rare during an inspection. However, there are many ways in which the company being inspected can make things difficult for the inspector. You need to be aware of these tricks and have your own remedies to get around them: Time-wasting (by long meetings, people not being available or even special lunches) can be defused by threatening to extend the time scale for the inspection until the whole programme is complete. Avoid being side-tracked (another time-wasting device) by having a clear programme from the start and sticking to it. We have already discussed provocation – do not let it upset you and on no account lose your temper. If you do, you lose control of the situation– and you reduce your credibility as well. Avoid being given an unrepresentative sample by insisting on taking samples yourselves, whether it is finished packs or documentation; if the company is allowed to choose, you will only see the perfect examples. If the excuse for a problem is that “this is a special case and does not normally happen” – take note of the circumstances and keep looking. In other words, establish whether there is a trend. If it is indicative of a problem, there will be more evidence during the inspection. If it really is a special case, there will be no more examples. If you get into a circular argument, accept that you are unlikely to get anywhere and move on.

The Inspection World Health Organization 24 November, 2018 Company Strategies – II Tricks Remedies Trial of strength Be firm; know your facts Insincerity Ignore it Pity Sympathize; carry on Absentees Call for deputy Amnesia Go back and get it yourself If one of the people being inspected tries to turn the situation into a trial of strength, don’t be pulled into the game. Ensure that you have your facts straight and remain calm. If the response you are getting from the person being interviewed is obviously insincere – ignore it; it won’t affect how you carry out the inspection or the observations you make. If someone tries to make you pity him or her, by telling you how hard done by he/she is or how difficult the job is – sympathize and then move on. Do not let it affect your objective judgement of how that person operates within the company. If the person you need to see is unobtainable for some reason – don’t let it upset your schedule. Call for his/her deputy and keep insisting until someone is found who can answer your questions. Finally, be prepared for sudden outbreaks of amnesia – it is amazing how many times people promise to provide something and then forget. If that happens, go back to the department in question and ask for the item yourself.

The Inspection World Health Organization 24 November, 2018 Group Session 3 On arrival, you are met by one of the company Vice-Presidents. You waste some time before starting the inspection, as they want to make a presentation of the company to you first. They had also planned lunch at a restaurant and some of the key persons of the departments you want to inspect are not available. What went wrong? How could it have been avoided? Use examples from your own experience to illustrate how you can handle situations where the manufacturer wants to prevent you from doing a thorough inspection. Now we are moving into the final group session. For the situation referred to on the slide, discuss what went wrong and how it could have been avoided. If possible, use examples from your own experience to show how you would handle things differently.

GMP Inspection Process

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GMP Inspection Process

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