An inspector calls – maintaining good manufacturing practices

Few within the pharmaceutical industry would dispute that good manufacturing practices (GMP) have become a more complicated undertaking in recent years.

Today's guidelines - as issued by various regulatory agencies - primarily take into account the manufacturing, testing and safety of drugs, so as to ensure they are fit for patient consumption.

But, as is the very nature of the pharmaceutical sphere (with its emphasis on development and progression), regulatory frameworks are never set in stone and are liable to be changed or altered.

Then there are disparities to be considered; one only need look at the increasing application of active pharmaceutical ingredients (APIs) in traditional drugs. For instance, since October 2005, legislation has been in place across the European Union that stipulates that APIs used as starting materials in dose form must be manufactured in compliance with EU GMP.

However, in some cases - often referred to as 'atypical activities' - materials named as APIs may be commercially manufactured or used in other products, as well as drugs. Consequently, there remains something of a grey area for small-dose-form manufacturers with regard to these 'atypical' APIs, and whether or not they are required to comply fully to existing GMP standards.

Ongoing efforts to standardise certain procedures across international markets have also left their mark on GMP compliance.

Perfect harmony

Established in 1990, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a tripartite project that brings together the respective pharmaceutical regulatory bodies in Europe, Japan and the US.

Over time, certain ICH quality guidelines, including ICH Q7 - a GMP guide for API usage - have been adopted by several regulatory bodies, including the FDA and, more recently, the European Commission.

"In the EU, there have probably been more changes to GMP regulations and directives in the last decade than in the previous 50 years," says Richard Bonner, chairman of the European QP Association, an interest group of the European Compliance Academy. "It has been phenomenal, and has been influenced by the likes of increased standardisation. This means companies really need to stay up-to-date with the expectations of regulatory agencies."

The most effective way of enforcing and ensuring GMP compliance among manufacturers is through inspections - as carried out by respective supervisory authorities. In the EU, inspections are coordinated by the European Medicines Agency (EMA); FDA is responsible for audits in the US.

In mainland Europe, initial GMP inspections take place when a pharmaceutical company applies to the EMA for marketing authorisation of a new drug - known as pre-approval inspections (PAI).

After a PAI is conducted, EMA inspections are scheduled in most cases, as opposed to unannounced (as is common practice in the US). The latter only tend to occur in Europe as part of a 'for-cause' audit, which is set up in the event of a company being suspected of fraudulent criminal activity, or because of an unexpected increase in adverse events, or even due to a whistlebower informing the regulators of non-compliant activities.

Best behaviour

So, how can personnel best ready themselves for the inevitable inspection? According to Bonner, compliance to GMP should be considered to be a basic prerequisite and in-built across the fabric of every pharmaceutical company, rather than a kind of manufacturing fillip.

"Really, a company should operate as if it was going to have an inspection every day of the week," he says. "It shouldn't be forgotten that GMP is a minimum standard - it's not the thing to aim for; it's the thing to start with. If you are operating to GMP compliance, you really shouldn't have a problem with regulatory authorities.

"What you need to be able to do is demonstrate to the authorities that you know what your business is, what the critical control points of your processes are, and what likely risks are associated with what you are manufacturing."

It would therefore seem that the more technical knowledge a pharmaceutical group can demonstrate, the less stressful the inspection will be. And, given the rising currency of GMP, there appears to be no shortage of industry bodies able to provide advice on how better to plan for an inspection.

Operating out of Heidelberg, the ECA is one such outlet. Founded in 1999 as an independent membership association with a focus on quality assurance and GMP compliance, it presently has nearly 4,000 members across Europe who are able to access its GMP-inspection databases - which relate to the EMA and FDA.

GMP in action

Made a foundation in 2010, one of the ECA's main objectives, according to its website, is to "promote the move towards a harmonised set of GMP and regulatory guidelines, by providing information and interpretation of new or updated guidances".

"The ECA covers all aspects when it comes to GMP and inspections," explains Bonner. "We run conferences for industry representatives and for certain members of the regulatory authorities, who frequently sign up to our courses. We also offer in-house training to companies, in which we dispatch one or two lecturers to visit them and spend a few days concentrating on GMP - whether it be the basics or more complicated stuff."

Such guidance has undoubtedly been welcomed by industry players - especially given that inspections have become tougher in recent years. Aside from the complex nature of regulatory frameworks, shop floors are now increasingly required to boast a knowledge of operations that transcends solely the technical.

"One of the biggest expectations for today's manufacturers relates to understanding risks," says Bonner. "I would say risk assessment is now almost a prerequisite for demonstrating that you not only know where the big problems could occur during manufacturing, but how to control them, too. There are far more expectations these days that people understand the technical side of production - it's not just about shovelling powders and following a recipe."

Then there's the shifting role of qualified persons (QPs), such as Bonner. Under EU pharmaceutical regulation, no batch of medicinal products can be sold on the marketplace without certification from a QP - who would normally be a licensed pharmacist, biologist or chemist with several years' experience working in manufacturing operations.

The QP has also the responsibility for the release of investigational medicinal products (IMPs).

Pivotal role

Last year notably saw the revision of the EU-GMP guideline Annex 16, designed in direct response to the swelling number of QP responsibilities. The new draft - titled "Certification by a Qualified Person and Batch Release" - has been revised to reflect the globalised nature of pharmaceutical supply chains and new quality-control strategies.

In layman's terms, QPs are about to see their job responsibilities multiply in the near future, as Bonner explains.

"You cannot underestimate the role of the QP," he says. "The QP is the only person who can place a product on the marketplace within the EU. Every company must have one - either under its direct employ, or under contract. And, with new regulations, such as Annex 16, their roles and responsibilities are increasing dramatically. This new annex states that 'it is the personal responsibility of the QP to certify a batch (in compliance with MA and EU or equivalent GMP and local/destination market laws)'."

The fact that a large amount of starting materials and APIs used within the European pharma industry originate from foreign markets, such as China and India - which are governed by different regulatory agencies - complicate these responsibilities even further.

"The QP has to have assurance that these materials have been manufactured to EU - or EU-equivalent - standards," says Bonner. "Companies are trying their utmost to deal with these changes in the law, but they have the potential to pose huge problems."

Bonner's words of caution are certainly worth heeding. GMP will, without doubt, continue to shape-shift over time in line with new pharmaceutical trends - such as globalisation and improving safety.

Consequently, inspections can be expected to become more rigorous, as regulatory bodies take a harder line. Companies that fail to comply will do so at their peril, and may well require as much counsel as possible to address new legislations. Expect ECA membership numbers to spike in the near future.