GMP Inspection Process World Health Organization 14 November, 2018 Types of GMP Inspection This module deals with the different types of drug regulatory authority inspection. It is a quarter-day session, split into activities as follows: Presentation 30 minutes 45–60 minutes Group discussions Plenary 30–45 minutes

Types of GMP Inspection World Health Organization 14 November, 2018 Objectives 1. To review the different types of inspection 2. To examine when each is appropriate 3. To discuss inspections in your country There are three main objectives of this session: Firstly we will review the different types of inspection that are carried out by regulatory authorities. Secondly, we will look at the situations when each of these types of inspection is most appropriate. Finally, we will discuss the drug regulatory authority inspections in your country and review any specific issues relating to them.

Types of GMP Inspection World Health Organization 14 November, 2018 Objective of the inspection Routine inspection Concise inspection Follow-up inspection Special inspection Quality systems review The objective of the inspection influences the inspector’s planning, organization, method of work, and the format of the report that will be written after the inspection. Different types of inspections can be performed depending on the objective of the inspection. Types of inspections identified in the WHO text, include: Routine inspection Concise inspection Follow-up inspection Special inspection, and Quality systems review. Let’s look at each of these types of inspections in more detail.

Types of GMP Inspection World Health Organization 14 November, 2018 Routine Inspection Full inspection of all components of GMP Newly established manufacturer Renewal of a license Changes:  new product or product lines  modifications to manufacturing methods  key personnel, premises or equipment History of non-compliance with GMP Not inspected in the last 3-5 years A routine inspection is a full review of all aspects and components of GMP within a facility. The inspector should also be aware of the licensing provision. Routine inspections may be announced or unannounced, depending on the history of the company, previous inspections and the policy of the country. It is appropriate to perform a routine inspection under the following circumstances: When there is an application for a new manufacturing license for a newly established manufacturer When a manufacturing license is due for renewal. If there have been significant changes such as new products or new product lines, modification to manufacturing methods or processes, or changes in key personnel, premises, and or equipment. If the company has an history of non-compliance with GMP. If an inspection has not been carried out within the past 3–5 years.

Types of GMP Inspection World Health Organization 14 November, 2018 Concise Inspection Consistent record of compliance with GMP Focus on limited number of GMP requirements selected as indicators Identify significant changes Indicate attitude towards GMP Non-compliance should trigger comprehensive inspection A concise inspection is the evaluation of limited aspects relating to GMP compliance within a facility. (It is known as an abbreviated inspection in some countries.) A limited number of GMP requirements are selected by the inspector to serve as indicators of overall GMP compliance by the manufacturer. The inspector also has to identify and evaluate any significant changes that could have been introduced by the manufacturer since the last inspection. Collectively, the selected indicators and identified changes indicate the manufacturer’s attitude towards GMP. Depending on national practice, a company would normally not be warned in advance about a concise inspection. A concise inspection is applicable under the following circumstances: Where a manufacturer has a consistent record of GMP compliance through routine inspections in the past. Where a sample of aspects can be taken as a good indication of the overall level of GMP compliance. However, if the concise inspection uncovers evidence that the level of GMP compliance has fallen, a more comprehensive or full GMP inspection should then be performed soon after the concise inspection.

Types of GMP Inspection World Health Organization 14 November, 2018 Follow-up Inspection Reassessment or re-inspection Monitor result of corrective actions 6 weeks to 6 months after initial inspection nature of defects work undertaken Specific GMP requirements not observed not adequately implemented A follow-up inspection is also referred to as a re-inspection or a re-assessment of the manufacturer. A follow-up inspection is performed specifically to monitor the result of corrective actions of the manufacturer following a previous inspection. The manufacturer would not necessarily know in advance about the follow-up inspection. Depending on the nature of the defects and the work required, the follow-up inspection could be carried out between 6 weeks and 6 months after the original inspection had taken place. The inspection is limited to specific GMP requirements that have not been observed or that have been inadequately implemented by the manufacturer.

Types of GMP Inspection World Health Organization 14 November, 2018 Special Inspection Spot check focusing on one product, a group of related products specific operations, e.g. mixing, labelling Complaints or recalls Adverse drug reactions Marketing approval or export certificate Information or investigation specific information advice on regulatory requirements There are a number of circumstances in which special visits or inspections may be necessary. A special inspection is undertaken to do spot checks. Spot checks could focus on one product, a group of related products, or specific operations e.g. mixing, or labeling. The manufacturer may or may not be aware in advance of the inspection, depending on the reason for it. If there have been complaints about a specific product that suggest there may be defects, then a special inspection could be performed to investigate the quality defects of the product. It is unlikely that the company would be warned in advance in this case. If there has been a product recall, this can also trigger an inspection, as would adverse drug reactions. In the above cases, the inspection would focus on the specific product or aspect of production that is suspect. An application for a marketing authorization or an export certificate may also trigger such an inspection. A special inspection could also be performed to gather specific information, or to investigate specific operations of the manufacturer. In some cases, this opportunity is used to advise the manufacturer on specific regulatory requirements. (The trainer should provide specific examples of “special inspections” e.g. after receiving a complaint, etc)

Types of GMP Inspection World Health Organization 14 November, 2018 Quality Systems Review Assess the quality assurance (QA) system Description of the QA system (e.g. manual) Policy and standards to be observed Management structure implementation Procedures quality standards set for products correctly defined manufacturing processes records kept QC and QA functions are performed The purpose of a quality systems review is to review the manufacturer’s quality system and to describe whether that has been shown to operate satisfactorily. The quality systems manual is a document describing the quality systems and the standards to be observed. It also includes the entire operational process, and the quality management policy and quality assurance approach of the manufacturer. The manual reflects the process of implementation of the quality policy, keeping of records, quality control and other quality assurance activities. This type of review is similar to that which is carried out when a manufacturer is applying for accreditation, e.g. international standards (ISO 9000).

Types of GMP Inspection World Health Organization 14 November, 2018 Frequency of Inspections Depends on type of inspection Inspectorate resources (e.g. workload, number of inspectors) New facilities - before licensed All companies - regular schedule ideally annual Large companies several visits over a period, e.g. 5 years validity of manufacturing license or GMP certificate Although there are ideal timetables that should be achieved for inspections, in practice there are a number of factors that influence the frequency of inspections. These are: - The type of inspection being undertaken. - The number of inspectors available and their workload. - The number of companies to be inspected. An ideal timetable would be an annual inspection of each manufacturer. The size of the manufacturing site will also influence the frequency of inspection. A large company with a wide range of products and several major departments may be inspected in a number of stages over a time period taking cognisance of the period of validity of the manufacturing license or GMP certificate.

Types of GMP Inspection World Health Organization 14 November, 2018 Duration of Inspections Depends on type of inspection Inspectorate resources (e.g. workload, number of inspectors) Size of the company Purpose of the visit Days to weeks Number of inspectors including specialist support The length of an inspection is determined by a number of factors, including the type of inspection to be performed, the number of inspectors, the size of the company and the purpose of the inspection or visit. An inspection can be performed over a period of a few days to several weeks. The time taken will also depend on the size of the inspection team. One or more inspectors can perform the inspection and the inspector(s) may request a specialist to accompany them during the inspection. Depending upon the area or specific aspects to be inspected, a specialist could provide specialist support to the inspection team. This can be very helpful in certain cases, e.g. the manufacture of biologicals.

Types of GMP Inspection World Health Organization 14 November, 2018 Announced and unannounced inspections Depends on type of inspection Announced comprehensive inspection Unannounced routine inspection (depending on country policy) concise inspection follow-up inspection special inspection Inspectors have to decide whether the inspection to be performed, will be announced or unannounced. This is dependent on the type of inspection, and the policy of the regulatory authority. A comprehensive inspection can be announced or unannounced. Concise inspections, follow-up inspections and special inspections are normally unannounced.

Types of GMP Inspection World Health Organization 14 November, 2018 Regulatory Actions Based on national regulations Correction of unsatisfactory situations Closing down of a factory Withholding of authorizations Product recall The inspectorate of a regulatory authority normally has certain powers to allow for regulatory actions. The regulatory actions are based on and controlled by national legislation The purpose of the regulatory action is to ensure that unsatisfactory situations in manufacturing sites are corrected in the interest of the public by ensuring that safe, effective, quality pharmaceutical products are manufactured. These powers or regulatory actions often include: - Closure of a facility (only used in an extreme case where a health hazard is perceived) - Suspension or revoking of the marketing authorisation. - Delay in approval of licenses or marketing authorisations. - Delay in issue of a GMP certificate. - Initiation of a product recall.

Types of GMP Inspection World Health Organization 14 November, 2018 Group Session The inspectorate received a complaint that an injectable product (water for injection (WFI), 10ml ampoule) is possibly contaminated with microorganisms. You have to organize an inspection of the company in question What type of inspection would be performed? Will the inspection be announced or unannounced? Who will be part of the inspection team? What will you consider in preparation for the inspection? We will now move into syndicate discussion. In your groups, discuss the situation in which 5 deaths are known to have occurred due to pseudomonas-contaminated WFI. Who would you take with you? What objectives would you have? Would you announce your visit? What actions would you take?

Types of GMP Inspection World Health Organization 14 November, 2018 Possible Issues Purpose of the inspection Notification (or not) of the company in advance Make-up of the team Programme for the inspection Sterility test, leak test and visual inspection Validation and qualification Documentation review The organization of the inspection will depend on the purpose - initial, routine, follow-up, concise etc. Whether the company is informed of the intention to inspect will depend on the purpose of the inspection and also on common practice within the country. Depending on the nature of the inspection, there will be times when the inspection team will not have all the necessary expertise and will need to bring in a specialist. For example, in the pseudomonas question, it might be necessary to involve a microbiologist to review sterile procedure or an engineer to review the design of the facility. Although there will be a programme developed before the inspection begins, it will often be necessary to revise that programme in the light of initial findings. Inspectors should be flexible enough to adapt the programme if necessary, but should also ensure that they are not deflected from their objectives by the company being inspected.