Computer Systems in China - to Validate or Not?

At today's Computer System Compliance session at the ISPE-CCPIE conference in Beijing we considered the new draft SFDA GMP regulations and the requirements (or not) to validate computer systems.

As blogged yesterday, the Chinese State FDA (SFDA) are committed to improving compliance, but the current draft of the new Chinese GMP regulations are ambiguous with respect to computer systems validation.

While certain Articles and Annexes infer a need to validate, calibrate etc certain control and monitoring systems there is no equivalent to US 21 CFR211 subpart 68 or PIC/S / EU Annex 11, which states a clear requirement to validate computer systems.

Some would claim that this is deliberate ambiguity on the part of SFDA and that it suits them to provide some 'wriggle room' for Chinese manufactures, but more likely is that computerized systems have been of relatively low priority. Re-writing and updating the GMP regulations is a significant undertaking and it is only reasonable that focus is given to basic GMP, especially when China is only just catching up with more developed countries with respect to the use of computer systems and there is no history and significant risk to patients as a result of failure to validate a computer system.

However, this ambiguity does not meet the stated aim of SFDA, which is to generally align national GMP regulations with World Health Organizations (WHO) guidelines. WHO guidelines (WHO Technical Report Series 937, 2006: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Appendix 5) clearly have a requirement to validate computer systems, and this does appear to be missing from the current draft of the SFDA regulations.

There is also a view that SFDA want to limit the costs they are imposing on their local manufacturers at a time when the Chinese government is looking to reduce the cost of drugs and devices while at the same time as it is looking to provide healthcare to 900 million people.

However, if SFDA is serious about building a risk-based approach into the new GMP regulations it is perfectly feasible to include a clear requirement to validate computer systems while leveraging a cost effective risk-based approach which will limit the costs involved in computer systems validation according to risk.

Unless this is included in the new regulations Chinese companies face the prospect of a two tier approach to computer system validation depending on whether products are intended for the domestic or export market. This would be confusing, limit flexible operations and potentially cause problems where Enterprise Systems support domestic and export operations.

Let's hope that SFDA take on-board the need to align with international regulations in this regard and revise the current draft regulations to provide the clarity that the Chinese Life Sciences industry is looking for with respect to computer system validation.

Regulatory Changes In - and For - China

There were some interesting sessions at this morning's keynote sessions at the ISPE-CCPIE conference in Beijing.

The Chinese State FDA presented a brief history of the Chinese GMP regulations, comparing these to other international regulations (e.g. WHO) and although they provided an outline of the new Chinese GMP regulations there was no commitment in terms of a date by which these will be made effective.

Cynics at the conference suggested after the session that this is because 90% of local Chinese companies would not comply with the new Chinese GMP regulations, but while the SFDA do appear to be keeping their options open regarding timing (and appear to be moving away from introducing a target date with a period of grace during which companies could move to compliance) a session from the US FDA gave a different picture.

Its 12 months since the US FDA set up shop (a field office) in China and although there are still only seven full time FDA staff in country - with only half of these conducting for-cause and high priority inspections - there appears to have been good progress in working with the Chinese State FDA (SFDA) as well as some of the Provincial FDA offices.

What we appear to be seeing is the Chinese authorities committing to address the regulatory/quality concerns that threatened to impact their export markets last year while also starting to address the reform of regulations in their home market, recognizing that the latter will take a while to address in a market consisting of literally thousands of (rapidly consolidating) manufacturers and distributors.

The US FDA and SFDA now meet on a monthly basis, with the SFDA acting as observers to some US FDA inspections. The US FDA is helping to fund training for the SFDA, reviewed the pending Chinese GMP regulations and have provided 10 GCP regulations for the SFDA to translate. This is all part of the US FDA strategy of helping to educate other regulatory agencies on the requirements of the US market and to help build inspection capacity (through the education of a cadre of SFDA inspectors trained in international regulatory expectations).

At the same time, multinational Life Sciences companies are sharing concerns about Chinese products with the US FDA, who are in turn discussing issues with the SFDA and there is also agreement between the US FDA and SFDA to focus on ten high risk products (mainly pharmaceutical, but some medical devices).
This co-operation provides evidence of the US FDA's desire to work more effectively with other regulatory agencies and will certainly start to address concerns about Chinese product.

At the same time it will also help the Chinese authorities to better regulate their own market, which is forecast to be world's largest by 2013 (behind the US and Japan). While 'rogue traders' operating out of China will undoubtedly be of continuing concern with respect to product quality and counterfeiting at least problems with the legitimate market are starting to be addressed.

Whatever people may think about the Chinese governments method of implementing change, there is no doubt that effective reforms can be implemented and probably more quickly than in many other markets. Although this is just the beginning there is no doubt that regulatory change is happening - which will be good for patients in China as well as the rest of the world.

What’s in a (Unique) Number?

Over the past eighteen months I’ve been contributing to a hefty tome which focuses on supply chain management in the pharmaceutical sector, specifically looking at some of the regulatory issues associated with information systems and information technology.

Amongst the issues I identified as still requiring resolution was the need to be able to more effectively track products through the automated supply chain in order to counter the growing problems of counterfeiting, to reduce dispensing errors and to better support product recalls.
The good news is that in the time it has taken to write, review, edit and publish a book there has been significant progress by various industry bodies and regulators in defining what is needed in terms of:

• Uniquely identifying product at multiple levels, down to the final package or device,
• Establishing databases to share information and reduce duplication of data
• Leveraging existing standards such as GS1 Healthcare Standards

This not only includes drug products but also medical devices and while there is still a way to go with respect to international harmonization the increasing adoption or incorporation of standards such as GS1 means that it should be possible for manufacturers to develop internal identification codes that can be used internationally in the commercial supply chain and also meet the various requirements of different regulatory bodies.

While there is still a long way to go with respect to tackling specific issues such as how to label a re-usable, sterilizable medical device or how to label combination products it seems as if solutions are within the grasp of the industry – a fact borne out by the number of large pharmaceutical and medical device companies now investing considerable sums of money in developing solutions.

Regulators are accepting that any regulations should be indepedent of any specific technology and that sensible exceptions (or alternatives) may be required for specific product profiles or devices.

However, to truly develop and deliver workable and cost effective solutions it is necessary to look beyond the basic information technology that assigns and registers identification numbers, prints and scans and compiles data bases.

Much of the discussion is currently being driven by technology vendors who have admittedly gone a long way to making such solutions possible. However, there appear to be very few technology vendors who are looking at the big picture. It also appears that individual pharmaceutical and medical device companies focus upon specific aspects of the full end-to-end solution, depending on the specific experience and ‘hot buttons’ of the teams looking at these solutions. While some teams focus on how to use RFID others are concerned about how relabeling should be managed, but I've seen relatively few companies putting everything together to deliver not just regulatory compliance, but real business advantage.

While information technology will of course underpin any serialization, track ‘n’ trace or electronic pedigree solution it is information systems that will deliver efficient and cost effective solutions.

This requires that Regulated Companies look beyond the printers, laser etching, label stock, etc and take a look at the strategic information flows and business processes that will be needed to make these technologies work as a business solution.

This requires a strategic review of:

• Product master data management, at multiple levels and across all geographies - addressing the critical issues of consistent product codes and the federation and synchronisation of products codes between systems,
• Serial number allocation, management and security on a global basis - remembering that real time solutions will need to work even while the Internet connection to some central database is down,
• Changes to packaging and labelling operations, which may restrict the flexibility that some organizations are used to - it will no longer be possible to assemble-to-order or label in country unless unique serial numbers can be generated at the right point in the supply chain,
• Modifications to business processes to support serialisation - including necessary changes to supporting transactional applications such as MES, ERP and CRM systems,
• Integration of systems ranging from printing, labelling and scanning systems at the bottom end, through MES and into ERP systems at the top end – and the realignment of the supported business processes,
• Collaborative working with third parties including contract manufacturers, customers and regulators – ensuring that identification data is available to trusted and authenticated users while assuring the security of individual serial numbers. 

These key business challenges need to be addressed while at the same time tackling the necessary information technology challenges. As even small pilots have discovered, relying on people to populate this data is extremely time consuming and inefficient - in many cases we're talking about maintaining tens of thousands of product codes and serial numbers into the hundreds of millions. To work properly solutions will need to rely upon internet services and service oriented architecture (SOA) – and area where the Life Sciences industry has been lagging behind other industries.
With regulatory deadlines (e.g.now looming in the US and Europe Life Sciences organizations are now starting to address the issue seriously – but let’s just hope that it isn’t too late. While it is certainly possible to implement partial solutions in time to meet key regulatory milestones unless these issues are tackled at a strategic business level the cost to industry may well outweigh the benefit in terms of risk mitigation.

IT Implications From A Shift in Regulatory Focus

At yesterday’s ISPE GAMP® UK Forum meeting it was interesting that while the usual regulatory roundup included the usual feedback from Regulated Users who have undergone regulatory inspections of their GMP and GDP areas, there was also a perceived shift in emphasis.

While a number of GMP inspections did look at some computer systems related issues (reviewing validation plans and reports, disaster recovery plans, test protocols, change controls and the like) this appeared less detailed than is usually reported and there were a couple of interesting things of note:

• A significant number of inspections weren’t looking at computer systems validation in detail,
• There was significant discussion around enforcement actions in other parts of the business, specifically in sales and marketing.

As last weeks coordinated action against counterfeit products in the supply chain showed, there is a growing concern with what is going on outside reputable manufacturing. These actions were coordinated by Interpol and supported by industry bodies, national law enforcement agencies and regulatory agencies, resulting in the seizure of more than 1 million tablets, 76 individuals now being actively investigated and leading to the closure of almost 300 websites (with more to come).

Reputable companies may not be the focus of such activities, but regulators have other concerns with regards to what respectable pharmaceutical companies are doing as part of their everyday business and which is perceived as also putting patients at risk.

As highlighted in an opinion piece in last week’s New Scientist (written by Dr Paul Thacker, in the 16th October edition) the increase of off-label prescribing is potentially placing patients at risk, and this is increasingly likely where pharmaceutical companies exercise less than tight control on the activities of those selling their products. As a result of the US Health Reform Bill, from 2013 companies will be required to disclose payments to doctors in excess of $10 and explain why the payment was made.

All of this means that regulations and enforcement actions are extending into almost every part of a Life Sciences company. However, very few companies are prepared to deal with this situation and fail to see that Information Systems can be both a blessing and a curse.

A well-defined and ‘validated’ computerized process can enforce actions that comply with regulatory requirements and can also significantly ease the burden of regulatory reporting. However, computerized systems that are poorly defined, insecure and easy to by-pass allow people to operate outside of the regulations, either mistakenly or by intent.

As such, Life Sciences companies should be looking to leverage experience from the GMP and GDP areas, where the validation of computerized systems is, for large parts of the developed world, a way of life. To rise to these new regulatory challenges it will however be necessary to:

• Take a sensible, cost effective risk-based approach, recognising that GMP and GDP systems are usually of much higher risk and that techniques will need to be adapted to suit lower risk profile systems and applications
• Recognize that the risk is inherent within the overall business and take an approach that considers the computerized system and information technology as just one element of the overall business process and information system (remembering that information also exists in other forms).

When used wisely, information technology can help Life Sciences companies respond to the changing regulatory landscape in a cost effective manner, delivering business improvement and supporting compliance.

The other side of the coin is that we can expect increasing regulatory focus and enforcement when the regulatory issues associated with the use of websites, collaborative portals, social networking sites, CRM systems and the like are ignored.

On the positive side, Life Sciences companies have time to respond and think about how to strategically leverage the knowledge and experience that already exists within other domains within the industry (GMP etc). On the downside is that few appear to be thinking about this at a strategic level just yet. Only time and on-going enforcement actions will tell how long any period of grace will be.

 

Marked Decline in Sponsored Link Advertising following US FDA Enforcement

An interesting recent piece of news was that sponsored link advertisements for pharmaceutical products have declined more than 50% following a spate of Warning Letters from the US FDA. According to various new articles published on March 26, 2009, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) sent warning letters to 14 major pharmaceutical manufacturers identifying specific brands as being in violation of FDA fair balance guidelines. The letters stated that sponsored link advertisements for specific drugs were misleading due to the exclusion of risk information associated with the use of the drug.

Most of these companies quickly removed their sponsored ads for these products and others not specifically mentioned in the letters. As a result, the number of sponsored links for pharmaceutical brands has dramatically declined as manufacturers changed their strategies to ensure compliance.

This illustrates neatly what we have been pointing out for some time; there is nothing special about the Internet as far as regulation is concerned. Advertising on the Internet is governed in the same way as advertising using any other medium, and non-compliance with the rules that govern advertising will be dealt with similarly.

This poses a challenge on a number of levels for the companies concerned. The very nature of sponsored link advertisements mandates brevity. In a magazine you can have your ad on one page and the list of warnings in small type on the next page or two, but how is this to be handled in a sponsored link of 25 words or even fewer?

This isn’t the only problem with on-line ads. They might be a common sight to US-based consumers but on a global stage they are unusual. In fact the only countries that I know of where direct-to patient advertising is permitted are the USA and New Zealand. Other countries such as the UK specifically prohibit advertising of Prescription Only Medicines to non-health professionals. This places the onus squarely on the regulated company to make sure that they target their adverts correctly otherwise they risk action from other regulatory bodies and not just the FDA.

For more on this topic see the Business & Decision webcast "Controlling Life Sciences Promotional Activities on the Internet"