Inspection and enforcement under the Medicines Act

 
The Pharmaceutical Journal
Vol 266 No 7131 p85-88
January 20, 2001

By Douglas Simpson, MRPharmS

A key element in the system that seeks to ensure the quality of the medicines used in the United Kingdom is the inspection and enforcement division of the Medicines Control Agency. The then editor of The Pharmaceutical Journal (Mr Douglas Simpson) visited the MCA at its London headquarters last year to find out how the division went about its business. He met the head of the division (Dr Gordon Munro), the head of inspection (Ms Linda Ambrose), the head of policy and standards (Mr John Turner), and the head of enforcement (Mr Norman Greenaway)

Douglas Simpson: What is the range of work undertaken by the inspection and enforcement division?

Gordon Munro: We are organised into four groups plus the British Pharmacopoeia. The groups cover inspection, enforcement, laboratories and licensing, and policy, borderline and standards.

We manage the BP on behalf of the Department of Health and both the secretariat and the laboratory are part of the division. The inspections group deals with good manufacturing and distribution practice (GMP and GDP), good practice in clinical trials (GCP) and good laboratory practice (GLP). The enforcement group investigates alleged breaches of medicines regulations. The laboratories and licensing group [headed by Dr Ged Lee, who was not available at the time of the interview] looks after the provision of laboratory services to the agency, handles manufacturers? and wholesale dealers? licences and includes the defective medicines reporting centre and the export certificates scheme. The fourth group deals with policy, borderline substances and standards. It also deals with internal self audit and proposed new directives and other European Community work.

How many people are involved in inspection and what kinds of background do they have?

Linda Ambrose: There are 35 people in the inspection group. Three focus on good laboratory practice; they have a two-yearly cycle of inspecting facilities carrying out toxicological and other preclinical safety studies, not only with pharmaceuticals but also foods and cosmetics. Three people are carrying out good clinical practice (GCP) inspections under what is at the moment a voluntary scheme anticipating the clinical trials directive. The rest of the group is focussed on GMP and GDP.

All staff are graduates, primarily pharmacists, chemists, biologists, doctors and biochemists. They must have a minimum of five years? relevant experience in a manufacturing operation or within the National Health Service in an appropriate function or in a toxicological environment if they are looking at GLP studies. They are all registered with the Institute of Quality Assurance as lead auditors. All the staff that do GMP inspections are on the register of those eligible to be named as qualified persons should they be operating in industry.

Do you find it easy to recruit inspectors?

LA: We had a good number of applicants last time we advertised. We will, incidentally be recruiting again soon because we have a couple of vacancies. The manager of our East Grinstead office recently left to return to industry, and some people are due to retire soon.

What kinds of facility are inspected?

LA: The full range, from small scale manufacturing pharmacies within the NHS, with only one or two staff, making specials or clinical trial supplies, to the major manufacturers. We inspect manufacturing facilities on a two-yearly cycle, irrespective of size. There may be an occasional inspection in between if we are doing extra work or carrying out an unannounced inspection. We inspect wholesalers on a four-yearly cycle.

When and why would you carry out an unannounced inspection?

GM: There may be something we want to look at. A good example would be when there is a particular problem, such as the use of excipients of bovine origin. We may inspect a site after a defective product recall. Sometimes we may only stay half a day. Other times it will be a full inspection.

LA: When an inspection is announced, managers make checks to ensure that everything is fine on the day. We like to do a percentage unannounced so that we can see the operation as it is working on a daily basis. We have always done this.

John Turner: You could ask – since manufacturers have to comply with GMP at all times – why should inspections be announced at all. The answer is, of course, that it may be useful to see particular people or a particular process, and we try to minimise any disruption, subject to us being able to do our job properly.

Can you outline the steps taken in a typical inspection?

LA: If it is a new application, we would consider whether the new facility was appropriate to manufacture the products concerned and that sufficient suitably qualified staff were in place and capable of operating to the appropriate standards. So we would make an initial inspection. Following on from that we would usually make two-yearly inspections. If it is a new site, we would consider the site master file. If it was an existing facility, we would revisit our notes from the previous inspection.

We tend to have the same inspector inspecting the same facility for a period of time so that there is a familiarisation with the activity and we can build up a working relationship with the people we are inspecting. Then, from time to time, we change the inspectors because it is always useful to have a new pair of eyes looking at a facility.

How many inspectors go on a visit?

LA: Routinely it is one, but it could be up to three. On complex sites or on overseas inspections, more than one inspector will go so as to shorten the time on site. For some sites, such as those dealing with radiopharmaceuticals, an inspector might be accompanied by a specialist.

What happens when you get there?

LA: We have a meeting with staff at the site to declare our intent. We do not go with hidden agendas. We are quite open about why we are there.

We carry out the inspection, continuously giving feedback and then review our findings with staff at the end.

Have you ever turned up and decided to shut a plant down straight away?

JT: Occasionally products have been quarantined instantly. This is where we have had reason to suspect that there is something seriously wrong with a product or batch of a product.

LA: If there are serious critical issues then the company is generally persuaded to cease operations voluntarily. If there is a serious risk to public health, it is our experience that the organisation voluntarily ceases manufacture immediately. Action is then taken to amend or suspend its licences unless satisfactory improvements are made. We have the authority to suspend a licence and stop manufacturing immediately.

What kinds of standard are applied?

LA: We are looking to see that people meet the requirements of their licences, including compliance with the European directive on GMP (95/316), which is set out in the Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distributors, Stationery Office, 1997). Some procedures are harmonised with other member states through the Pharmaceutical Inspections Co-operation Scheme (PICS). We also look, where appropriate, for compliance with the Guide to Automated Manufacturing Practices (GAMP). Irrespective of whether we are in the UK or overseas, we apply the same standards.

GM: We have our own quality assurance system, which sets out procedures and practices and training requirements. We are also independently audited by the British Standards Institution and are registered as complying with the International Standard for Quality Systems (ISO 9002).

LA: Sometimes, people may experience an inspector bringing along a colleague, who is auditing him or her. So, we inspect the inspectors doing the inspections. Each inspector is audited every year, usually by someone from the policy and standards group or a regional manager from another of the division?s regional offices.

How many regions are there?

LA: Four. We have the North West of England and Wales region, based in Chester, the North East of England and Scotland, with an office in York, the Midlands, with an office in Hitchin, and the South, with an office in East Grinstead. They share the overseas inspections. The Hitchin office, for example, generally inspects in Japan and China and the Far East.

Is inspecting an art or a science?

LA: Both. People use their understanding of processes and products, so there is a scientific aspect to it. Inspectors also develop a gut feeling, partly from their own work experience and partly from their experience as inspectors. There is a kind of intuition that tells them where to look. All inspectors see all types of operation, so they have a broad understanding of what happens within industry and the Health Service.

What kind of co-operation do you get from the industry?

LA: Excellent. I think we have a good working relationship with commercial organisations and the Health Service. We routinely have liaison meetings and consultation meetings with the hospital sector and industry, and professional bodies also.

What happens if an inspection shows that good manufacturing standards are not being met?

LA: Following an inspection, there is always a close-out meeting where the inspector will deliver his or her findings. There should never be surprises at these meetings. Because of the dialogue during inspection, things that we have mentioned as we have gone round have often been dealt with by the time we are due to leave and we can make a check on any changes there and then.

Following the inspection, the inspector will return to his office and write a post- inspection report and a letter to the licence holder or applicant. One of five different types of letter could be written.

A type 1 letter indicates that the site is generally compliant, but that there are a few minor deficiencies. (It would be exceptional to go to any facility and to find nothing that could be discussed.) The company then has 28 days to respond. Assuming a satisfactory response, and possibly an additional inspection, the inspector will then send a type 5 letter to the effect that the inspection is concluded satisfactorily and the site is in general compliance with GMP.

For a type 2 letter to be sent, there may be several minor deficiencies and maybe a major one – we categorise deficiencies as ?critical?, ?major? or ?other? – some of which may have continued from a previous inspection. A type 2 letter is a little more strongly worded than a type 1. Satisfactory responses will lead to a type 5.

A type 3 letter will usually follow the discovery of several major and even a critical deficiency or be a consequence of failure to rectify a continuous deficiency. This will be countersigned by a manager.

And then there is the type 4 letter. In this we tell a company that our findings are of such a serious nature, either because of consistent failure to comply with GMP or because they are critical, that we are recommending that action be taken against the site?s licence. Such a recommendation is considered by the inspection action group, which comprises medical assessors, pharmaceutical assessors, and legal and policy advisers. The group considers the inspector?s findings, the legal requirements and the risk to public health. The group makes its recommendations to the head of inspection and enforcement for approval.

Would the manufacturer be able to present to the group as well?

LA: The licence holder or overseas manufacturer is informed of the proposed action and normally has 28 days in which to make proposals for remedial action or to contest the findings and decisions.

Does this type of situation arise often?

LA: No. It normally arises when a company consistently fails to put its house in order. We prefer to work with organisations to help them resolve problems.

How much reliance is placed on overseas inspection processes to ensure that products reaching Britain have been made to GMP standards?

JT: Within the European Community, there is mutual recognition of manufacturing authorisations across the community and of the inspections that are undertaken to support them. The regulatory authorities of the member states may exchange inspection reports. The EC, including the UK, has mutual recognition of inspection with Australia and New Zealand. Agreements with Canada and Switzerland are about to be put into operation. And we are in negotiation with the United States and Japan. Where there is a mutual recognition agreement in operation with a country, we recognise that country?s GMP compliance. For all other countries wanting to send medicines to the UK, we would inspect.

Which countries do you go to?

LA: The United States, mostly. Increasingly, India, Japan and South Africa. We have just completed our first inspection in China. It went very well – just a few minor deficiencies. Last year we did about 15 per cent of our manufacturing inspections overseas. The number is increasing.

Are you generally satisfied with the standards being achieved by manufacturers at home and overseas?

GM: Generally, yes. Overall, UK standards are very good. They have been fairly constant for the past three to four years. We have a suspicion that there could be a trend towards a greater number of serious deficiencies being found, but, given the two-yearly inspection cycle, it is too early to say.

Are there any concerns about any particular countries?

LA: I would not say that any of the countries we visit are generally any better or worse than the others.

JT: We would only inspect a relatively small number of companies in any one country – those wanting to send products to the United Kingdom – and so we only see a small part of the total. Generally, there are examples of good and bad practice in all.

What can be done to improve standards?

LA: Improvement is particularly needed in the areas of cross-contamination, packaging and labelling.

JT: Normally, we seek to ensure compliance with existing standards rather than change them. However, there is an intention to extend GMP to starting materials and clinical trial products, which are not covered at the moment. That will contribute to improved quality of products and hence the safety of patients.

GM: We also have to think about the standards themselves. With the move to biotechnology, we have to think about what is an appropriate standard for a manufacturing process that is radically different from a classical chemical synthesis.

LA: Increasingly, we are working with companies subject to amalgamation and major site changes to help with any compliance problems that they might encounter. Companies will notify us in advance that there are going to be major changes and sometimes this will trigger an inspection.

What else is inspected by the division and what resources are devoted to it?

LA: We offer a voluntary good clinical practice inspection scheme for the conduct of clinical trials that has been taken up by a number of commercial organisations and NHS operations in anticipation of the forthcoming European directive on clinical trials.

We also offer a voluntary inspection system for active pharmaceutical ingredients, again in anticipation of legislative changes. Companies introducing new chemical entities can ask for pre-approval inspections.

JT: We are working with the NHS Executive on an inspection scheme for human tissue banks.

GM: This is very much in its infancy. A draft code of practice is out for consultation at the moment.

What is being done by the division to test the quality of medicines?

GM: We test about 3,000 samples a year, mainly taken from community pharmacies. Most of the analysis is done at the Royal Pharmaceutical Society?s Medicines Testing Laboratory in Edinburgh. We tend to look at any one time at product types, such as dry-fill antibiotics, rather than choosing products at random. What this tells us is that the quality of medicines in Britain is very high.

Should testing be extended in any way?

GM: We are comfortable with what we have in terms of monitoring the quality of licensed medicines. We also take samples of unlicensed medicines. We have done two major surveys of traditional Chinese medicines, specifically products containing Aristolochia spp because of potential problems with aristolochic acid. We have also found traces of heavy metals and steroids in ethnic medicines.

We have the whole area of testing under continuous review.

JT: We maintain close links with the NHS quality controllers group. There is a lot of testing done within the NHS.

The defective medicines reporting centre falls within the division. How does this work?

GM: We get about 200 to 250 reports a year from a range of public and professional bodies and pharmaceutical companies about quality defects.

We assess whether or not there is a valid problem and the level of risk. While the responsibility for recall is the licence holders?, when needed we send out recalls or warnings by a cascade system. Technology is advancing rapidly and we are looking at ways in which we can communicate even more quickly and effectively.

Turning to another of the groups in the division, what kind of role does the enforcement group perform?

Norman Greenaway: We enforce the medicines regulations. It is a complementary role to that of the medicines inspectors. The way that we carry out our work is similar to police and customs investigation work. We start work when problems are suspected. Reports come from a variety of sources – medicines inspectors, other parts of the agency, doctors, pharmacists, members of the public, the Royal Pharmaceutical Society, and so on.

The subjects of enforcement fall into two categories: licence holders who may be infringing the terms of their licences or who have a licence as a convenient way of getting illegal product into normal distribution chains; and those who have no intention of holding a licence at all and seek a market for products with medicinal properties or for quack cures.

What are your particular problem areas?

NG: We have spent a lot of time in recent years on threats posed to the licensed distribution chains by illegal trade. We have seen large scale diversion of products and a few attempts to get counterfeit products into the distribution chain.

Is counterfeiting a problem in the UK?

NG: We think not. We think the risks are low. But we are not naive about it.

GM: From what we see in the medicines testing scheme and what we see in the inspection and enforcement group, the level of counterfeiting in the UK is virtually undetectable. It is a very rare occurrence. But we remain vigilant, because, on a world-wide basis, a significant level of counterfeit products is believed to be circulating.

What about prosecutions?

NG: Over the past eight years we have brought a steady number of prosecutions. We have had a 95 per cent success rate, which is high. But we are not a gung-ho prosecuting authority. There are other ways of doing things. We also use formal cautions, warnings and sometimes just advice – a proportionate response.

GM: The enforcement group is brought in if other attempts to resolve an issue fail or if the issue is clearly criminal.

Are pharmacists in your firing line very often?

NG: There was the recent series of cases where pharmacists were, quite literally, buying stock out of the back of a van. But more often than not, it is pharmacists who are helping us. We have conducted a number of investigations as a result of sharp-eyed pharmacists spotting something that was not quite right. The enforcement group is always pleased to receive direct approaches from pharmacists about such things. We can very quickly get a suspect product looked at by experts.

Can we expect any developments in enforcement?

GM: We have not done so yet, but we would prosecute where there is a breach of the advertising regulations. We have investigated a number of cases but they have been resolved before they came to court. We have looked particularly at the types of gifts and inducements offered.

We could prosecute where companies consistently failed to report adverse drug reactions or where there had been serious breaches of GMP regulations, but neither has happened yet. We try to be proportionate. Prosecution is the last resort, except in those cases where a really serious offence appears to have been committed. Decisions to prosecute are taken by the MCA?s prosecuting lawyers.

Can you outline the work of the group dealing with borderline substances, policy and standards?

JT: The work on borderline products is an operational activity, classifying preparations which are on or near the borderline between a medicine and something else, such as a food or a cosmetic. We have recently introduced a statutory procedure. We now have a panel of independent experts to hear appeals against preliminary decisions made by us.

So far as our policy work is concerned, a large part is giving advice on interpretation of the legal position to outside inquirers and internally within the agency. We are responsible for producing several agency guidance notes. Two recent ones have been on specials and borderline substances. We also provide considerable input into the work of the European Medicines Evaluation Agency and the European Commission, dealing with such matters as updating GMP requirements and the drafting of directives, such as those on clinical trials and starting materials. We have led the agency?s work in obtaining mutual recognition agreements on GMP.

With regard to standards, we maintain the division?s procedures and audit against them. We are independent of the operating divisions. We are responsible for much of the quality assurance of the work of the division. As part of this, we have introduced questionnaires to get feedback from licence holders and others that have been subject to inspection.

GM: Some of the most positive feedback comes from companies who have had the worst inspection results.

JT: We are keen to be increasingly open with companies and we have started a GMP consultative committee. We are hoping to put more documentation on to our website.

GM: We have just started publishing lists of all manufacturing licence holders and wholesale dealer licence holders. We have recently consulted widely on making available on request copies of inspection reports, suitably modified to remove commercially confidential information. We want to make sure that it is done in a way that is not prejudicial to the individual company.

We value the good relations that we, as the regulator, have with the industry. We can be tough, but it is much better for everyone if it does not get to that stage.

JT: We have long held the view that the majority of manufacturers and distributors want to do the right thing, and supply high quality products. In many ways, our insistence on good practice helps them to do that.

GM: That is certainly true of the UK. It makes life easier when industry is really trying hard to do a good job.

A good enough note on which to end, I think. Thank you.

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