HDA UK Media And Political Bulletin – 7 February 2017
The Financial Times, Jonathan Ford, 6 February 2017
The harmonised regulatory system progressively developed by the EU since 1995 has supported the UK’s success as a world leader in pharmaceuticals. Counter to sceptics’ arguments about the detrimental impact of Brexit, regulation risk in the sector might be overplayed. It can be argued that Britain’s strength in pharmaceuticals derives from numerous other factors, such as world-class research universities and a favourable fiscal regime. Single market legislation affects 100% of sales, including those that never touch Europe. It carries with it obligations that have nothing to do with pharmaceutical product safety. These burdens could be alleviated of lifted after Brexit. Post-Brexit, the UK could have greater optionality than at present. The UK could streamline processes to reduce the burden of compliance, and prioritise risk-based regulation and speed, thus potentially stimulating more research activity. There will be changes to the sector with Brexit, but it seems unlikely that regulation will pose a serious risk.
MHRA Blog, Alan Moon, 6 February 2017
Compliance issues at manufacturing and distribution sites form the subject of the MHRA’s latest blog post. The MHRA’s Inspection Action Group (IAG) is a regulatory tool to manage and protect public health. The group includes both medical and pharmaceutical assessors, legal advisors, enforcement representatives and senior inspectors. The Compliance Management Team (CMT) is another non-statutory process, devised in 2013. It is designed to prevent compliance issues by directing companies to a state of compliance, trying to avoid the need for regulatory action. The MHRA has freshly outlined the role and structure of its compliance management systems.
There is no Parliamentary Coverage.
MHRA Blog, Alan Moon, 6 February 2017
At the GMDP Symposium 2016, Andrew Hopkins and I gave a presentation about the Inspection Action Group (IAG) and Compliance Management Team (CMT), to highlight the systems and processes in place for when compliance issues are identified at manufacturing and distribution sites.
I began my presentation with a quick poll to see how many of the audience were aware of these processes, and was surprised that approximately 50% of the audience were not familiar with the
IAG process and approximately 70% of the audience were not aware of the CMT process. The purpose of this blog is therefore to provide an overview of the processes and possible outcomes, and to explain what happens on site when compliance issues are identified at manufacturing and distribution sites
Inspection Action Group (IAG)
MHRA’s primary role is to protect public health and the IAG process forms a regulatory tool to manage this. IAG are non-statutory multi-disciplinary groups which advise MHRA’s Director of IE&S on recommendations for regulatory action. There are two groups:
- IAG1 – which cover GMP, GDP, Blood industry cases
- IAG2 – which cover GCP, GPvP cases
This blog focuses on cases covered by IAG 1, however further information relation to IAG 2 is available here.
IAG1 meets fortnightly (usually the 1st & 3rd Tuesday of each month), however ad-hoc meetings may be called for urgent cases. The group includes both medical and pharmaceutical assessors, legal advisors, enforcement representatives and senior / expert inspectors. Depending on the specific cases being referred, there may also be input from specialist clinicians, VMD, EMA / MRA partners and USFDA as needed. A key consideration for the multi-disciplinary team in reviewing the case is the risk-benefit balance, as not having an essential medicine available could also cause harm.
Reasons for referral
The most common reason for referral to IAG is when critical deficiencies are identified during inspection process. Other possible reasons would be:
- Unable to contact licence holder
- Refusal to accept inspection
- Unacceptable applications or variations (e.g. refusal to name a QP)
- Inadequate responses to post inspection letter
- CMT case escalation
- Result of product recall / DMRC
- Issues raised by other EU Member States
- Outcome of Enforcement activity
The intention to refer a case to IAG as a result of inspection issues will have been discussed during the course of the inspection and the inspector would explain reasons for the referral during the inspection closing meeting. The post-inspection letter is reviewed and signed by an independent senior member of the inspectorate. All correspondence from then on is via the IAG Secretariat, however the inspector is still involved in all aspects of the case and review of follow up information but all communication is through one channel. If the referral is not directly from an inspection, then the letter to the company/licence holder comes directly from the IAG Secretariat.
Possible outcomes from IAG 1for UK sites could include:
- Refusal of licence / variation or an existing licence being revoked.
- Requesting a QP or RP to justify their actions and potentially lead to their removal from a licence.
- Request a company to attend a meeting at the MHRA offices.
- Potentially the issuance of a statement of non-compliance with GMP – more typically a conditioned statement of non-compliance and a restricted GMP certificate – limiting activity to certain dosage forms or particular manufacturing lines only in order to maintain the supply of a critical medicine under closer supervision.
- Referral to Enforcement if evidence found of – fraudulent data, harmful product, falsified medicines.
Third country sites do not hold Manufacturing Authorisations (MIA) but are still subject to inspection and issuance of GMP certificates following successful inspections and must be named within a Marketing Authorisation (MA) in order to supply products into the EU. Where these sites are referred to IAG, possible outcomes include:
- Refusal to name the site on an MA, or possible removal from an existing MA.
- Issuance of a statement of non-compliance with GMP.
- For voluntary or triggered API or IMP inspections, the site could be removed from the respective MA or CTA.
- Proposed suspension, variation or revocation of licence.
Where it is proposed to suspend, vary or revoke a licence, the company/licence holder can make written representation and request a person appointed hearing. However, if a statement of non-compliance is issued, there is no right of appeal.
Follow up actions as a result of IAG referral could include:
- Immediate targeted re-inspection relating to continued supply of critical medicines.
- Re-inspection to review corrective actions after the QP has provided confirmation that the site is ready for re-inspection.
- A short-dated GMP certificate could be issued.
- Continued monitoring by IAG and request for regular updates on action plan
- Increased inspection frequency
- For serious and persistent non-compliance, possible consideration of prosecution under the Human Medicines Regulation 2012, Clinical trials Regulations 2004, or Blood Safety & Quality Regulations 2005 as applicable.
Compliance Management Team (CMT)
CMT is also a non-statutory process and is managed within the Inspectorate by senior and expert inspectors, operations and unit managers rather than the wider multi-disciplinary team of IAG.
Initially devised back in 2013, the compliance management approach was established to point out the ‘compliance icebergs’ on the horizon, in particular those that companies were failing to see. This can create time to change course and stop a ‘titanic’ issue occurring.
The CMT meets on a monthly basis or ad-hoc as required, and was established to provide a mechanism to escalate case management and direct companies to a state of compliance. The main objectives for CMT are to protect public health, maintain supply of medicines and try to avoid the need for regulatory action. However, this does not mean that CMT will take on the role of consultant and fix the issues for you!
Reasons for referral
Referrals to CMT are made when an inspector has significant concerns regarding a site’s compliance status but there is no immediate evidence of a critical deficiency or the need to propose regulatory action. The referral may also be as a result of inadequate responses to deficiencies noted from an inspection.
The intention to escalate a case to CMT as a result of inspection issues will be discussed during the inspection closing meeting. The inspector refers the deficiencies to a CMT representative for review and discussion. The review process ensures objective oversight by senior staff where a high number of deficiencies may be raised and ensures consistency between inspectors.
The post-inspection letter is reviewed and issued by a senior member of staff from the Inspectorate and a shorter timeframe for the company’s response is required, typically 21 days from receipt of the letter. At this stage, the communication remains between the company and the site inspector with oversight from the CMT representative, although ad-hoc communication such as letter to the company CEO may be sent from CMT.
Next steps and possible outcomes following a CMT referral may include:
- Increased inspection frequency and / or request for regular compliance reports to monitor progress against the agreed action plans.
- If acceptable progress is not made, then this could result in a referral to the IAG for consideration of regulatory action.
- The aim is to guide the company back into a state of compliance such that they are then put back onto the routine risk-based inspection process.
- Another aspect of the process – ensure objective oversight by senior staff where a high number of deficiencies may be raised and ensure consistency between inspectors.
So what happens on site when compliance issues are identified?
As soon as the inspection team thinks there is a possibility of escalation they will stop the inspection and let the site know. This pause gives the site the chance to inform the right people and plan their strategy. The inspection team will look for additional information to mitigate the risk which may come from less formal processes e.g. email correspondence not included as part of
investigation report. The inspection team will also want to know the potential impact of supply issues on the patient and what markets are supplied, e.g. just UK, or all EU and MRA partners.
As I have already mentioned, the intention to refer a case to either IAG or CMT as a result of inspection issues will be discussed during the inspection closing meeting. The lead inspector will read out a script from an information sheet and confirm the deficiencies identified, to make sure the site understand the severity of the issues and escalation process. The inspector is not expected to read the information sheet verbatim during the closing meeting, although they will ensure that the content is discussed with senior company representatives and provide either an electronic or paper copy of the sheet.
The legal basis for action differs for each licence type, and so a copy of each relevant information sheet will be left with the site in cases where multiple licences / activities are relevant to the proposed action. I have included below links to the text from the information sheet that would be used to brief a UK MIA, MIA(IMP) or overseas manufacturing site if they were being referred to either IAG or CMT, to give you some idea of the level of information that is provided to the site.
Since the two escalation processes were introduced, a wide variety of cases have been referred across different licence types, dosage forms, licence activities, and have included:
- Laboratories and manufacturers
- Finished product and API manufacturing sites
- Overseas and UK sites
- Licensed and unlicensed products
- Medicines and blood products/components
The number of new referrals to IAG and CMT are as follows:
Number of IAG Cases (new referrals)
- 2012 – 23 GMP
- 2013 – 21 GMP
- 2014 – 12 GMP
- 2015 – 12 GMP
- 2016 – 10GMP
Number of CMT cases (new referrals)
- 2014 – 15 GMP
- 2015 – 18 GMP
- 2016 – 16 GMP
The key message we gave at the symposium was that whilst both processes seem to be working reasonably well, we do not want to take regulatory actions any more than you want us to! So, hopefully this post is all just interesting information and you never have to have experience of either process!
From Factory to Pharmacy
As part of our mission to build awareness, understanding and appreciation of the vital importance of the healthcare distribution sector, we developed an infographic explaining the availability of medicines. It identifies the factors that can impact drug supply, as well as the measures that HDA members undertake day in, day out to help mitigate the risks of patients not receiving their medicines.See the Infographic
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