This section answers frequently asked questions on Good Manufacturing Practice (GMP) risk-based inspections.
Compliance report/ interim updates
1. Do interim updates for an importer need to come from the importer or the 3rd country manufacturing sites also?
2. Does the Marketing Authorisation holder have to provide interim updates or compliance reports?
3. Do major changes through the Manufacturing Authorisation variation process need to be reported on a compliance or interim report?
4. What signatories are required on compliance and interim reports?
5. Can the Site Master File and compliance report not be combined?
6. If an interim report changes the next inspection due date why will the site not be informed until the inspection is arranged?
7. If compliance report changes are significant in number would time spent on inspection be changed at the last moment?
8. How does the content of the compliance report differ from the Site Master File updates provided before inspections?
9. What is the role of the Qualified Person (QP) for compliance reports and interim updates?
10. How will MHRA ensure consistency between what MHRA inspectors require via the compliance and interim reports?
11. What triggers submission of the initial compliance report?
12. If a company has not declared a change in a compliance or Interim report but at an inspection the inspector deems the change to be significant will this result in a deficiency and how will it be categorised?
13. Who would be expected to sign compliance reports for pharmacy manufacturing units associated with large trusts?
14. What is the difference between the compliance and interim reports, they look very similar?
15. When in relation to implementation of a change should I submit an interim report?
16. Should changes reported in the compliance or interim reports be restricted to GMP changes only?
17. What feedback can we expect from inspectors following submission of an interim report?
Freedom of Information
1. Will manufacturing sites be able to see a contract laboratory's GLP risk score?
2. My understanding is that the Annex 1 risk assessment will not be made available under Freedom of Information? Has MHRA taken legal advice on this?
GMP compliance certificate
1. Will the certificate of GMP compliance still have a 3 year life even if inspection frequency is tighter?
2. Will a GMP certificate be issued after each inspection for sites with a risk rating of 0 or I?
Miscellaneous
1. How will MHRA educate companies/senior management that risk rating is not necessarily a direct correlation to how compliant a site is?
2. What is the impact on MHRA resource of the new reporting requirement?
3. Are 3rd country Investigational Medicinal Product (IMP) inspections in the scope of RBI?
4. New sites are stated to be followed up within 12 months. Does this apply to 3rd country sites such as US Food and Drug Administration (FDA) approved sites?
5. Do you intend to inspect Marketing Authorisation holders who do not hold a Manufacturing Authorisation but contract out manufacturing and control services i.e. virtual pharma?
6. Will this mean that inspectors will be assigned to specific sites and will conduct re-inspections of that site?
7. Will there still be unannounced inspections?
8. How will the process work for large sites that typically get multiple inspections to cover each area of the facility?
9. Will RBI be applied to Active Pharmaceutical Ingredients (APIs) in future?
10. Will there be a requirement to disclose the reports of internal audits?
11. Is a change in site for a warehouse deemed as a new application on a risk basis although it would be covered under a license variation?
12. What benefits/ measurable changes do MHRA expect to see using this system?
13. How do the MHRA link virtual organisations to contract manufacturing sites?
14. Is there any intention to combine inspections of various areas of super sites (>250 GMP related staff) as a result of RBI?
15. Will the Marketing Authorisation holders get copies of inspection reports for sites named on MAs?
16. Was it considered to have a closer link between risk level and type of operations undertaken e.g. Aseptic?
17. Does the RBI system apply to Blood Establishments?
Multiple sites/licenses
1. Where a company has multiple sites conducting the same processes using common systems will this be taken into account via the RBI system?
2. How will risk ratings of GMP, GDP and GPvP be linked?
3. Will GMP assessment of Phase 1 Clinical Trial commercial sites be conducted jointly by GMP/GCP in future?
4. If more than one license type (e.g. MS, MIA(IMP)) is held on a site would the site receive different risk ratings for each?
5. Where does the type and content of license and subsequent site activity feature in the risk planning process?
Other agencies
1. Will there be a harmonised approach with European Medicines Agency (EMEA) / The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PICS) e.g. for manufacture of centralised products?
2. Are there plans to share this approach with US FDA and do they plan to use this approach?
3. Are the inspectorates of Mutual Recognition Agreement (MRA) countries in agreement with the potentially reduced inspection frequency?
Risk rating assessment/score
1. Will it be obvious to sites what influences the final risk rating between level of compliance and type of operations undertaken?
2. Why does the level IV and V risk not inspect after 36 months in line with the GMP certificate life?
3. What is a complex site?
4. How many minor deficiencies make a major, will there be uniformity among inspectors?
5. Do the MHRA full inspection reports go through a peer review as the risk ratings will?
6. Where peer review is required for higher risk sites will the reviewers be identified to the site?
7. How will MHRA link batch specific variations to the manufacturing sites?
8. What happens to those sites that have continued risk assessments that rate them as high risk?
Compliance report/ interim updates
1. Do interim updates for an importer need to come from the importer or the 3rd country manufacturing sites also?
The interim reports in this case are for the Importer only, the 3rd country manufacturing sites are required to submit their own reports for changes affecting their sites. This also applies to Compliance Reports.
2. Does the Marketing Authorisation holder have to provide interim updates or compliance reports?
No the reports are required from the importer and the 3rd country manufacturing sites in line with the inspection schedules of the sites.
3. Do major changes through the Manufacturing Authorisation variation process need to be reported on a compliance or interim report?
No changes that are flagged through the Manufacturing Authorisation variation process need be reported through the compliance or interim report systems.
4. What signatories are required on compliance and interim reports?
The person completing the report and the person responsible/accountable for the performance of the site - this is likely to be a CEO or Managing Director or Site Director etc.
5. Can the Site Master File and compliance report not be combined?
At present the decision has been taken to keep them separate. They serve different purposes and it was felt that combining them could create more work than it may save. In particular the signatories may be different and having a single document may be more complex to handle. However this will be further considered during the first review of the process in Q4 2009.
6. If an interim report changes the next inspection due date why will the site not be informed until the inspection is arranged?
It is intended that there is no formal publication of a new inspection date following submission of an interim report. However it is anticipated that there is general informal communication by the inspector with the site ( either by e mail or telephone conversation) regarding the impact of the interim report.
7. If compliance report changes are significant in number would time spent on inspection be changed at the last moment?
As the compliance report is used for inspection planning the number and type of changes reported may have an impact on inspection content and duration. This would be addressed on a case by case basis and may in some circumstances result in an extended inspection or additional visit. However it is not anticipated that there will be much change from historical practice.
8. How does the content of the compliance report differ from the Site Master File updates provided before inspections?
It is still required that an up to date Site Master File is provided prior to the inspection, the content of the compliance report is related to various changes in facilities and performance and not necessarily covered by the SMF. The informal advice of changes since the last inspection is replaced by the compliance report.
9. What is the role of the Qualified Person (QP) for compliance reports and interim updates?
There is no requirement for the QP to sign either report however they clearly need to be aware of the changes that happen and are reported - this may happen through the company's change control or management review processes etc.
10. How will MHRA ensure consistency between what MHRA inspectors require via the compliance and interim reports?
The guidance document and examples provide a level of guidance to both industry and inspectors on what changes should be reported. Sites should be prepared to justify what they do and don’t regard as significant. MHRA will also be building this into the process review in Q4 2009.
11. What triggers submission of the initial compliance report?
This will be requested by the inspector on the pre-inspection letter.
12. If a company has not declared a change in a compliance or Interim report but at an inspection the inspector deems the change to be significant will this result in a deficiency and how will it be categorised?
Firstly it should be emphasised that MHRA inspectors will be pragmatic on discovery of any such issues and seek to understand the site's rationale. Where this seems reasonable no further action will be required. Where relevant changes are deemed to have been withheld either deliberately or inadvertently by a site this will be recorded as a comment in the post inspection letter and report. Where the inspector has reason to believe that the site has not been entirely open the inspector has the option to record the incident as a contributing discriminatory factor and use this to increase the risk rating of the site.
13. Who would be expected to sign compliance reports for pharmacy manufacturing units associated with large trusts?
Firstly the person completing the report and secondly the person responsible and accountable for the facility. This may likely be the Chief Executive of the trust.
14. What is the difference between the compliance and interim reports, they look very similar?
The compliance report is linked to the inspection preparation and contains an additional page for sites to provide an indication of any future changes in a two year window. The interim report is very similar, but without the forthcoming changes section and should be used for reporting actual changes between inspections.
15. When in relation to implementation of a change should I submit an interim report?
The interim report can be submitted as soon as the change is confirmed as approved at site level and an implementation date has been set. In some cases e.g. redundancies MHRA understand that staff and shareholders need to be aware first but the interim report should be submitted at the latest as soon as the change is 'public' or at the point a risk to GMP compliance and patient safety may be presented. If interim reports are submitted after changes have been made the report should be submitted as soon as is practicable after the implementation date.
16. Should changes reported in the compliance or interim reports be restricted to GMP changes only?
Full guidance is provided on the MHRA web site and this requires only GMP type changes to be reported. However it should be noted that this includes some changes that may not be immediately regarded as GMP e.g. senior staff and organisation changes - New Site Director, New CEO, change of legal owner of the company etc.
17. What feedback can we expect from inspectors following submission of an interim report?
Inspectors should acknowledge your report and seek further clarification as required. Inspectors will not formally communicate the impact on next inspection date although it is anticipated that informal communication by e mail or telephone will take place. Sites may not be aware of this until the inspection is scheduled.
Freedom of Information
1. Will manufacturing sites be able to see a contract laboratory's GLP risk score?
It is not MHRA policy to release risk ratings other than to the site they apply. As such the score would only be available if shared voluntarily by the laboratory.
2. My understanding is that the Annex 1 risk assessment will not be made available under Freedom of Information? Has MHRA taken legal advice on this?
The inspection report including annex 1 will be issued through FOI requests however it is likely that most of the content of Annex 1 will be redacted such that the final risk rating can not be identified. Advice has been received from MHRA solicitors in formulating MHRA approach to disclosure of RBI under FOI.
GMP compliance certificate
1. Will the certificate of GMP compliance still have a 3 year life even if inspection frequency is tighter?
Yes, certificates will reflect the fact that the site is generally GMP compliant and as such will carry a 3 year life. They will not reflect the fact that a surveillance inspection may be conducted more frequently than 3 years.
2. Will a GMP certificate be issued after each inspection for sites with a risk rating of 0 or I?
Yes, assuming that the site's license continues to be supported.
Miscellaneous
1. How will MHRA educate companies/senior management that risk rating is not necessarily a direct correlation to how compliant a site is?
By use of seminars like this one, information on the MHRA web site and through discussion during inspections between the inspector/ site nominees.
2. What is the impact on MHRA resource of the new reporting requirement?
It is early in the implementation phase at present however it is envisaged that inspectors will be able to absorb the small amount of increased work into their schedules, indeed the system was developed with impact on MHRA and industry in mind.
3. Are 3rd country Investigational Medicinal Product (IMP) inspections in the scope of RBI?
3rd country IMP inspections are conducted on a voluntary basis and so do not come under the scope of RBI.
4. New sites are stated to be followed up within 12 months. Does this apply to 3rd country sites such as US Food and Drug Administration (FDA) approved sites?
This will be dependent on a number of factors; The purpose of a follow up on new sites is to see evidence of systems in operation in relation to EU products/ GMPs. Where a 3rd country site is new to MHRA (EU) but has been manufacturing products to a similar standard for some time prior to the inspection then this may provide such evidence. Inspectors will take into account the individual circumstances when finalising the risk rating and next inspection period. Where no relevant history is available then re-inspection within 1 year is likely to be required. Note this has not historically been applied consistently to 3rd country sites.
5. Do you intend to inspect Marketing Authorisation holders who do not hold a Manufacturing Authorisation but contract out manufacturing and control services i.e. virtual pharma?
The RBI process is between the MHRA and the Manufacturing Authorisation holders or 3rd country manufacturing sites. There will be no requirement on Marketing Authorisation holders (MAH) to complete RBI forms. However during the inspections the agreements and linkages with the MAH are examined and may impact the overall risk rating of the site. On occasions it may be necessary to review regulatory/GMP controls directly with the MAH.
6. Will this mean that inspectors will be assigned to specific sites and will conduct re-inspections of that site?
Inspectors have always been assigned to specific sites, although these have been changes frequently in some cases in recent years due to the increased recruitment of MHRA inspectors. MHRA plan to retain some continuity by having an inspector complete 2-3 inspection cycles with a site wherever possible.
7. Will there still be unannounced inspections?
RBI does not change the use of unannounced inspections. These have and will continue to be conducted where a specific cause or reason is identified. The RBI process will be used with compliance reports requested during the inspection.
8. How will the process work for large sites that typically get multiple inspections to cover each area of the facility?
During the first overall cycle (currently 2 years) the site will be assessed against RBI criteria related to each individual inspection but the risk rating will not be finalised until after the last inspection. The sites will be required to provide interim reports after the first inspection and compliance reports on subsequent inspection. Inspection reports will be issued after each inspection.
9. Will RBI be applied to Active Pharmaceutical Ingredients (APIs) in future?
This depends to an extent on regulatory changes in EU and whether the requirements for inspection are amended. As API inspections are at present conducted on a voluntary or trigger basis only it has been determined that the RBI program is not applicable in its current state. A form of risk assessment is applied to situations where a triggered inspection is confirmed however this is out with the RBI process.
10. Will there be a requirement to disclose the reports of internal audits?
MHRA have no plans to examine internal audit reports. MHRA regard these as self improvement mechanisms that have to operate in an open manner within sites. MHRA would not want to inhibit this process by reviewing the reports.
11. Is a change in site for a warehouse deemed as a new application on a risk basis although it would be covered under a license variation?
RBI applies to all licensed facilities so any new facility on a license would be regarded as new and be assessed through RBI. The addition of the new site location would be picked up through the variation process rather than an interim report for an existing site.
12. What benefits/ measurable changes do MHRA expect to see using this system?
This is difficult to quantify. A general goal would be to increase compliance and protect patient safety but increased surveillance of lesser compliant sites could result in an increase in deficiencies recorded and Inspection Action Group cases which could be interpreted as poorer compliance. Overall we hope to have a structured approach to ensuring that resources are targeted appropriately and a greater understanding of and commitment to GMP compliance from key executives responsible and accountable for sites. Work is also planned to further define outputs and outcome measures as required by Hampton.
13. How do the MHRA link virtual organisations to contract manufacturing sites?
Manufacturing sites are identified on Marketing Authorisations, however it is the manufacturing sites only that are inspected although in some cases virtual sites require licenses because some licensable activity is conducted on site.
14. Is there any intention to combine inspections of various areas of super sites (>250 GMP related staff) as a result of RBI?
There is no fixed policy on inspection of super sites although typically these are inspected in 2 or 3 sub inspections in the UK but as a single larger inspection overseas. A flexible approach taking account of the best interests of MHRA and the site will continue to be adopted.
15. Will the Marketing Authorisation holders get copies of inspection reports for sites named on MAs?
MA holders will not receive reports directly from MHRA. It is expected that sites share this information under agreement with the MA holder.
16. Was it considered to have a closer link between risk level and type of operations undertaken e.g. Aseptic?
It was considered but MHRA feel that real risk level is more inherent in how individual sites manage and mitigate risk - this will come out of inspection findings. We therefore determined that it was not appropriate to have a system that deemed a higher risk from a manufacturer of aseptic products who operates in a highly compliant and safe manner than a non sterile solid dose site that is very non-compliant. In such a situation it is deemed to be a higher risk of patient harm from the solid dose site.
17. Does the RBI system apply to Blood Establishments?
The process does apply to sites holding Blood Establishment Authorisations. However due to the statutory requirement to inspect these no later than every 2 years this will be placed as a maximum inspection frequency. Otherwise the process will operate in the same manner and the risk rating will drive the next inspection date. In practice risk ratings III and IV are merged in terms of inspection frequency and rating V will apply with the exception of carrying a 2 year inspection frequency but retaining the reduction in time on site of up to 50%.
Multiple sites/licenses
1. Where a company has multiple sites conducting the same processes using common systems will this be taken into account via the RBI system?
The RBI system requires that individual sites are assessed rather than companies. However we would discuss approaches on a case by case basis and it may be beneficial to both MHRA and companies to streamline the process e.g. single interim update for a change affecting all sites rather than one per site.
2. How will risk ratings of GMP, GDP and GPvP be linked?
There is no plan to link the ratings or the systems. Where sites may have an MIA and WL license the GMP system will be used and only one complaince/interim report is required per site (not per license). Where sites also receive a GPvP inspection the two systems will operate independently although adverse results will be exchanged internally in MHRA and we would attempt to schedule inspections such that they don't coincide.
3. Will GMP assessment of Phase 1 Clinical Trial commercial sites be conducted jointly by GMP/GCP in future?
These inspections have already been transferred to GCP and GCP inspectors have been trained to cover manufacturing issues in these inspections. As such there is no plans to conduct joint inspections other than for training purposes.
4. If more than one license type (e.g. MS, MIA(IMP)) is held on a site would the site receive different risk ratings for each?
The risk rating applies to the site not the license so only one rating would be reported.
5. Where does the type and content of license and subsequent site activity feature in the risk planning process?
The license and activity is taken into account when planning the duration of the inspection and the number of inspectors and their skill set. This allows appropriate time for the inspection team to ensure an appropriate inspection is conducted and findings are proportionate to level of compliance and thus level of risk. Extra discriminatory factors can be incorporated where the inspector determines there is greater risk or risk has been well mitigated by the site.
Other agencies
1. Will there be a harmonised approach with European Medicines Agency (EMEA) / The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PICS) e.g. for manufacture of centralised products?
The current system applies purely to MHRA however it is envisaged that other competent authorities will develop systems. Although PICS are developing a guide to Risk Based Inspection there is no visibility of a single EU system on the horizon at present.
2. Are there plans to share this approach with US FDA and do they plan to use this approach?
This approach is currently developed by MHRA for sites where MHRA are the supervising authority. FDA are developing their own approach to use of risk assessments in planning and conducting inspections. MHRA will continue to share information with FDA on all aspects of pharmaceutical regulation and GMP.
3. Are the inspectorates of Mutual Recognition Agreement (MRA) countries in agreement with the potentially reduced inspection frequency?
The RBI system does not alter the historical opportunities by MHRA to increase or decrease inspection frequencies. The system now provides a formal objective mechanism to control and manage this. As a result there is no need to for MRA partners or other EU competent authorities to agree to the process.
Risk rating assessment/score
1. Will it be obvious to sites what influences the final risk rating between level of compliance and type of operations undertaken?
The full rationale used will be clearly recorded in the Inspection report annex that will be provided to the sites on close out of the inspection.
2. Why does the level IV and V risk not inspect after 36 months in line with the GMP certificate life?
We have set it as 30 months in order to allow for inspection scheduling (+/- 2 months) and inspection close out (up to 3 months). Sites should not be without a revised valid GMP certificate.
3. What is a complex site?
This would typically be a site where, as assessed by the inspector, the complexity of product types and any specific challenging technologies that the site utilises may result in a particular risk to GMP.
4. How many minor deficiencies make a major, will there be uniformity among inspectors?
There are clear definitions of inspection deficiency category that reflect the criticality of the deficiencies identified. Although there is no direct link between the number of 'other' deficiencies and a major deficiency it comes down to the judgement of the inspector when there is an indication that an aspect of the quality system is sufficiently deficient to fall in to the 'major' category. MHRA do recognise the need to ensure consistency between inspectors and will continue to work on ensuring consistency between inspectors.
5. Do the MHRA full inspection reports go through a peer review as the risk ratings will?
Peer review of reports is conducted during training of new inspectors and one year following initial sign off of a new inspector. Inspectors are audited by an expert/senior inspector which includes review of a report every 3 years. There are no plans for reports to be routinely peer reviewed other than the new Annex 1 under defined circumstances.
6. Where peer review is required for higher risk sites will the reviewers be identified to the site?
The peer reviewers and their comments will be identified on the Annex 1 form that will be provided to the site with the inspection report.
7. How will MHRA link batch specific variations to the manufacturing sites?
Information on batch specific variations is entered on the agencies Sentinel system by Product Licensing staff. It is recognised that in some variations the site of manufacture is not immediately clear. A solution to this problem and thus easier identification of manufacturing sites is being addressed.
8. What happens to those sites that have continued risk assessments that rate them as high risk?
MHRA expect that in working closer with higher risk sites it will lead to an increase in compliance and a reduction in risk. The higher the risk level the more frequent inspections and as these are charged at a daily rate inspection fee this is an additional cost to the high risk sites and should help drive greater commitment to compliance. For sites that operate at an unacceptable level of risk and particularly those where critical deficiencies are identified the sites are referred to the Inspection Action Group (IAG). Through IAG action can be taken against the sites license and in extreme cases the license can be suspended or withdrawn.
