Back in 2007 Eric Blumberg, Deputy Chief Counsel for Litigation said:

‘Companies MUST establish internal systems and controls to define,

MEASURE, monitor and ensure compliance’

Three years on, as Warning Letters and Consent Decrees hit an all time high, companies are clearly struggling to comply. Managing a Quality System without accurate and reliable measures of performance is a bit like a pilot trying to land without dials and gauges …very dangerous. As supply chains become even more complex regulators are expecting you to have ‘oversight’ of the Quality System by having accurate measures of performance. This highly interactive course will help

Now in its 3 successful year, our 2 day course on ‘Key Performance Measures for Quality Systems’

will show you how to

• Identify performance measures that that tell the truth and nothing but the truth. Measure that are accurate and sensitive and help you to make the right decisions
• Select measures that improve performance and stop fire fighting and crisis management
• Collect, interpret and act on information in hours, not days or months
• Use measures to focus your resources on areas that need attention
• Help you sleep easy at night knowing that you’re ‘in control

More information can be found in the attached PDF. The course will be presented on Tuesday 21 and Wednesday 22 September at the Manchester Marriott Victoria & Albert Hotel, UK.

Remember you are only as good as your last decision. Without accurate and reliable performance measures you can’t make accurate and reliable decisions. This course will show you how

Over 600 delegates have benefited from our course on ‘Human Error: Causes and Prevention’.  Feedback has been consistently outstanding…have a look on our website and see for yourself (‘Customer Feedback’ tab) delegates tell us our course is unique and the best available. They also tell us that the tools and techniques covered actually work in reducing the frequency and severity of human error!

To help you reduce costly errors and mistakes DBA will launch a ‘HELP’ group later this year. This will provide a forum for sharing ideas and best practice in ‘error reduction’. What’s more, membership is free. This is how it will work.

• Members will have free access to the latest information, regulatory developments, research, and practical tools and techniques for error reduction via our website
• Free membership is restricted to those who have attended our course on ‘Human Error: Causes and Prevention’. Access will be pass word controlled
• Applying for membership is simple. All you have to do is send us at least 3 examples of tools, techniques and methods you’ve used to reduce human error! These will be ‘anonymised’ and added to the appropriate section on the web page. If all eligible members applied you will have access to over 3,000 tools and techniques for error reduction. What a resource! Sections will include: 
    
  • A ‘discussion forum’ to post questions and ask for advice
  • The latest regulatory developments and requirements
  • The most recent academic research on error reduction
  • What other industries are doing to reduce human error
  • Practical tools and techniques submitted by members and proven to work.

What next? Well, in the next few months you will receive an invitation to join. If you don’t respond don’t worry, we won’t bother you again!

For those who share our passion for error reduction you will be just a few clicks away from potentially 3,000 solutions!

Reason for amendment

This document is a revision of an earlier document published in July 2001 as MEDDEV 2.4/1 rev 8. It includes information pertaining to the changes in classification resulting from the amending and implementing Directives issued since the last revision of this document in 2001, including derogation of the classification rules in the case of breast implants and hip, knee and shoulder joint replacements and requirements related to devices containing human blood derivatives and medical devices manufactured utilising tissues of animal origin. In addition this guidance document takes account of the changes arising from Directive 2007/47/EC2 which further amends Directive 93/42/EEC and became applicable as from 21st March 2010.

You can obtain the free publication at the following location.....

http://ec.europa.eu/enterprise/sectors/medical-devices/files/meddev/2_4_1_rev_9_classification_en.pdf

Like many, I’ve been following the media frenzy surrounding the disaster in the Gulf of Mexico with keen interest.

Just in case you’ve missed out, an oil rig exploded on April 20, 40 miles off the coast of Louisiana killing 11 people.  Since then over 5 million gallons of oil have been released into the Gulf of Mexico.  Attempts to stem the flow have so far failed.  At the time of writing they are on plan ‘G’!

The losses are incalculable. The families of the deceased, the environment and its precious wild life, local businesses and jobs, BP’s reputation, legacy and share price - all destroyed.

DBA’s course on ‘Human Error: Causes and Prevention’ emphasises the vital importance of learning from the mistakes of others…so what can we learn from this terrible disaster? Although the investigation is still ongoing vital facts are emerging:

• A litany of worrisome events and findings described in internal documents indicate that this disaster, like most, was preventable.  If only the early warnings had been heeded
• Up to 7 ‘system safeguards’ were in place to prevent this ‘blow out’ from happening. All failed.  BP would have benefited from a few accurate and reliable performance measures and a system of turning the data into action
• Complex and seemingly fail proof technical systems went wrong because of widespread ‘system failures’.  Their KPIs and other performance measures were either inadequate or ignored
• Congressional investigators revealed that a key system safeguard, known as the ‘blow out preventer’ failed because of malfunction.  Performance tests on the ‘BOP’, indicated that problems were identified which could lead to its malfunction.  These results, and other measures, were either ignored or simply not reported
• Although the details of the investigation will take many months to emerge, one thing is guaranteed; it will conclude that BP’s ‘Quality System’ failed big time

So What Can We Learn?

Pharmaceutical companies rely heavily on their Quality Systems to capture, contain and remove problems to prevent the release of defective medicines.  As the number of Warning Letters hits an all time high, anecdotal evidence suggests that many Quality Systems are no longer ‘fit for purpose’.  Look at any ‘483’ and you will find familiar reading:

• Repeat deviations, a product of poor investigations and implementation of effective CAPAs
• Overdue planned preventative maintenance
• Poor or inadequate change management leading to processes being operated outside validated parameters
• Lack of investment in training, generating operators who only know which button to press, but not why
• Failure to follow procedures
• Lack of QA ‘oversight’…failure of QA surveillance programmes (audit and self-inspection and the like) to detect problems early on

The VITAL Importance of Quality System PERFORMANCE MEASURES

What’s fascinating is that most companies are drowning in KPIs and other performance measures.  These should, in theory at least, prevent these types of problems from occurring. Since this is clearly not happening, companies are guilty of some, if not all of the following:

• Selecting poor, insensitive measures of performance that do not tell the truth, the whole truth and nothing but the truth
• KPI ‘blindness’.  Having so many measures that people, at every level, are overwhelmed by the data
• Poor reporting systems
• Data and knowledge simply not being translated into action.

If you suffer from these symptoms attending our course

KPIs and Performance Measures for Quality Systems

Manchester Marriott Victoria & Albert Hotel, UK

Tuesday 21 and Wednesday 22 September 2010

is a must!!

You Will Learn

• How to measure the performance of your Quality System (your ‘system safeguards’) easily and efficiently. Without these accurate and reliable performance measures you really shouldn’t be releasing product!

• How to select the 20% of measures that provide 80% of benefit. As far as measures are concerned ‘less is more’
• How to make sure these are accurate, reliable and sensitive
• How to collect, interpret and ACT on the information within hours, not days…weeks…or months
• How to use these measures to drive continuous improvement

A ‘DIY’ friend of mine told me that you ‘always measure twice and cut once’. In other words make sure you have accurate and reliable measures before you make any decision. As Quality Systems become even more complex it’s vitally important to have measures you can trust

This highly successful course will show you how

INTERNATIONAL CONFERENCE ON COUNTERFEIT MEDICAL PRODUCTS PAVES THE WAY FOR THE MEDICRIME CONVENTION                

Basel (Switzerland), 16.04.2010 - More than 140 participants, senior officials from health, law enforcement and judicial authorities from around 40 states, international organisations and institutions from around the world came together on 15 and 16 April 2010 in Basel to discuss the practical implementation of the future Council of Europe MEDICRIME Convention.

The MEDICRIME Convention is the first international instrument providing for the criminalisation of counterfeiting of medical products and similar crimes in order to protect public health and establishing a framework for international co-operation on criminal law matters between Parties in this regard.

Medical products in the context of the convention include medicinal products, medical devices as well as active ingredients and excipients used in the manufacture of these products.

The substantive criminal law provisions included in the MEDICRIME Convention cover not only the counterfeiting of medical products but also the supplying and trafficking thereof as well as the falsification of documents linked to medical products. In addition, they cover the manufacturing and supplying of medical products without authorisation.

The importance of international cooperation to successfully combat counterfeited medical products was underlined in the presentations and discussions.

More information is available at www.coe.int/medicrime

On April 28, 2010, the U.S. Food and Drug Administration sent a letter to companies and a wide range of other key stakeholders detailing the agency’s concern over cargo and warehouse thefts of FDA-regulated products.

The products stolen have included prescription and over-the counter medicines, medical devices, and infant formula.

In its letter, the FDA seeks to:

• raise awareness among industry about each firm’s responsibility to review and strengthen their security practices
• inform industry of the actions the FDA will take when the agency becomes aware of a large-scale theft, and outlines steps that firms should take
• emphasize the importance of notifying and informing members of the supply chain and the public after thefts occur.
  The FDA believes every company should have a clear plan developed on how to respond to these incidents, since swift action is essential.

The agency believes prevention of cargo theft is critical. To help achieve that goal, the FDA will continue to work closely with manufacturers and wholesalers to find ways to better secure the nation’s supply chain, which protects the public health.

I was at a company recently who suffered from procedural non-compliances big time. Not surprising really when you looked at what the operators relied upon for guidance and clarity, namely their SOPs.

Even for simple tasks they had to wade through pages of ‘purpose’, ‘scope,’ ‘definitions’ and other ‘blurb’ before they got to what really mattered; the specifics of ‘how to do’.  Even then, hopes of clear, concise and readable instructions were dashed because of:

• Too many ‘filler words’
• Complex and lengthy sentence structure. In fact, almost Shakespearian
• Multiple cross references to other documents most of which were unavailable
• No pictures, just boring words

Yes, the error rate was high but it should have been higher.  The operators were truly heroic in getting anything out the door.

What alarmed me most was that SOPs, designed to provide clarity and improve consistency, did the complete opposite.  Operators were distracted and confused by the very things sent to help them.

There is however a very simple answer. A very simple alternative…the humble checklist.

When faced with difficult and complex tasks, we humans are up against two main difficulties. The first is the fallibility of the human memory and attention; especially for routine tasks.  Even more insidious is the tendency for people to skip steps, often with serious consequences

Used widely by medics and pilots alike, instructions provided in checklist format prevent such failures and non compliances.  SOPs that are written for the user by authors with a checklist mindset work, providing you know what rules to follow.

You may be just one step away from dramatically reducing your error rate by simplifying your key SOPs and giving your operators some hope and save yourself a fortune.  If you would like to find out how, come along to our popular course on Human Error: Causes and Prevention.

Forthcoming courses:

Human Error: Causes and Prevention

18 - 20 May 2010

Crowne Plaza, Philadelphia Center, USA

Human Error: Causes and Prevention

14 -16 June 2010

Manchester Marriott Victoria & Albert Hotel, UK

If you would like further information just drop me an email - mkl@dba-global.com

Please click on 'more info'

As part of the EU implementation of ICH Q9 the Commission published a proposed revision of Part II of the EU GMP Guide (on APIs) in April 2008.  This revision is proposed to incorporate principles of Quality Risk Management as laid down in the ICH guideline Q9, which correspond to similar changes made to Part I, Chapter 1 of the Guide and published in February 2008.

The final version of this change was published in February 2010 is operational from no later than 31 July 2010.

The new section on Quality Risk management is introduced as Section 2.2. The remaining sections of Chapter 2 are renumbered.  No other changes have been made.  It should be noted that besides the implementation of ICH Q9 no additional changes are currently foreseen, as those would need proper discussion at the ICH level.

On 17 March 2010 several of the EU Compilation of Community Procedures (CoP) were updated to include a new procedure to ensure a co-ordinated response to serious GMP non-compliance for voiding/suspension of a CEP, as well as updated procedures on the “Handling of reports of suspected quality defects in medicinal products”, “Handling Rapid Alerts and Recalls Arising from Quality Defects” and “GMP Inspection report - Community format”.

The new Procedure on dealing with serious GMP non-compliance for voiding/suspension of Certificate of the European Pharmacopoeia (CEP) deals with all circumstances of serious GMP non-compliance, whether found at a manufacturing or import authorisation holder, third country manufacturer or active substance manufacturer is necessary to ensure a coordinated approach to potential risks to public/animal health.  It stresses that some actions may lead to consequential actions.  For example, if a manufacturing authorisation is revoked or suspended or a CEP is voided or suspended it will have an impact on one or more marketing authorisations.  Serious GMP non-compliance found at an active substance manufacturer means that manufacturing authorisation holders using the active substance in question as a starting material have failed to fulfil their legal obligations and therefore action may be taken against the manufacturing or import authorisation or QPs connected with it.  The actions that may be taken include:

 A Community notification of GMP non-compliance

• Withdrawal of GMP certificate or Issue of GMP certificate with restricted scope
• Action against a manufacturing or import authorisation
• Voiding or suspension of CEP
• Action in connection with marketing authorisations
• Impact on clinical trials
• Issuing of a Rapid Alert
• Prohibition on supply
• Disciplinary measures against the Qualified Person(s)

The CoP on Handling of Reports of Suspected Quality Defects in Medicinal Products was revised to extend the scope to include active substances/active pharmaceutical ingredients and falsified medicines.

The CoP on Rapid Alerts and Recalls was revised to change the mechanism of transmission of notifications from fax to e-mail, with Class I and II defects being circulated to all contacts on the notification list.  The scope was extended to include active substances/ active pharmaceutical ingredients and investigational medicinal products.

The Community format for GMP Inspection reports was revised to align the format with activities and amendments made in order to enable summary reports for European Medicines Agency inspections to be discontinued.

Note: it is this document that provides the definitions for the classifications used in EU GMP Inspection reports; i.e. Critical, Major and Other.

A revised version of Annex 6, Manufacture of Medicinal Gases, was issued in February 2010 and becomes effective on 31 July 2010.

One of the major drivers for this revision is the need to more clearly define what is to be considered a starting material and what is a bulk medicinal product, when dealing with medicinal gases.  The revised annex states “Normally, the production and purification steps of the gas belong to the field of manufacture of active substances. Gases enter the pharmaceutical field from the first storage of gas intended for such use.”

Other changes include the need to train sub-contractors and tanker drivers, more detail on requirements for storage of cylinders and mobile cryogenic vessels, the conduct of risk management on tankers used to transport medicinal gases and other measures to address cross-contamination concerns.

The guidance identifies SNI requirements at the package level only.  A “package” is defined as the smallest saleable unit.  Re-packagers are required to add a unique SNI if they change the “smallest saleable unit” from that of the manufacturer.

The Guidance does not address:

• How to link multiple SNIs
• Pallet or case level SNIs
• Implementation or application issues for SNIs

The guide calls for all drugs to be labelled using a standardised numerical identifier (SNI).  The proposal is that all packages should be marked with an SNI made up of a National Drug Code (NDC), as set out in the US Food and Drug Administration’s (FDA) 21 CFR part 207, and a unique serial number, which must be < 20 alpha numeric characters, generated by the manufacturer or re-packager.  This combination is referred to as a serialised NDC (sNDC).  An example is shown below:

Some biologics, such as blood products, do not have a NDC.  In these cases they may use other recognized standards for identification and labelling, such as ISBT 128, which creates a unique identification number for each product package.

The guide states that the SNI is NOT required to include batch numbers or expiry dates.  Also the location of the SNI on the package not specified.  However, it does state that the SNI:

• Must not obscure FDA required information
• The NDC and serial number locations not required to be contiguous
• Scanning / viewing should not damage package integrity

The SNI should be BOTH human and machine readable but the guidance is flexible on the data carrier technology to be used; e.g. 2-dimensional bar code, RFID, or other technologies that may be developed in the future.

This guidance is compatible with the serialised Global Trade Item Number (sGTIN) model set up by the international standards organisation GS1.  The FDA has been a key collaborator on the sGTIN system which, to date, has been adopted by 65 countries as a way of tracking pharmaceuticals.

The World Health Organization (WHO) has published a draft guideline for comment, entitled “Guideline for the Production and Control of Specified Starting Materials”.  This guidance provides both background and context for the information on “specified starting materials”, in March 2010.

WHO defines these materials as any substance which is primarily or mainly used as a starting material for the production of an API, but which itself could be used directly as an API.  WHO are concerned that if a material that itself could be an API is used as a ‘specified starting material’ then applying full API GMP and other requirements may by unnecessary and counter productive.  For example, if, in practice, the GMP regulations and pharmacopoeia monographs are effectively applied for the “specified starting materials” to some manufacturers in some countries but not in others, this could lead to a wide price differential between countries.  If access to the drug is limited due to the price, pricing level will always be driven by the lowest quality standards.  The replacement of a drug product by cheaper and sometimes dangerous substitutes, which may even cause deaths (less active drugs, false medicines), is the risk driven by high prices.

If the material is used in the production of an API then the quality attributes and specifications should be determined by the API manufacturer and the material should be fit for its intended use.  Viral safety and TSE data should be carefully considered if the starting material is animal derived.

Quality Control for compounds used as specified starting materials should address impurity profiles, isomers, residual solvents and other impurities that may be carried thru to the resulting API.

API manufacturers are encouraged to take a risk based approach in setting specifications for these materials, considering the number and type of unit operations between introduction of the material and production of the resulting API.

On Wednesday 3 March the EMA published a draft CHMP Guide on Real-time Release and a Concept Paper proposing a revision to the CHMP Guide on Process Validation.  These documents can be seen at http://www.ema.europa.eu/pdfs/human/qwp/81121009en.pdf and http://www.ema.europa.eu/pdfs/human/qwp/80911409en.pdf respectively.  The Concept Paper on Process validation makes no mention of any possible revision of Annex 15 of the EU GMP Guide, which also is in need of revision in order to introduce the concepts of Quality by Design and risk management.  These two documents show that the EMA are now moving in the same direction as the FDA on these related topics, all be it about a year or more behind them.

In early March 2010 the FDA released a new Guidance for Industry document on “Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications”.  This new Guide can be found at http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM202439.pdf

The UK’s Pharmaceutical Quality Group (PQG) has launched a guide on Supply Chain Risk Management.  This is a very good document that is available as a free interactive pdf.  Whilst it is aimed at supply chain risk management it also has a lot of very good general content on pharmaceutical quality risk management.  For more information on this guide and to download your free copy, go to http://www.pqg.org/publications/riskmanagement/index.php

Please find attached a document relating to the new EU Variations process as set out in Regulation 1234/2008.

The EU has published revised GMP guidance for Investigational Medicinal Products which was adopted by the European Commission on 31 January 2010 and published on 03 February 2010.  The deadline for coming into operation is 21 July 2010

• The revision reinforces the principle of independence between production and quality control functions in cases where the number of personnel involved is small.
• Changes to sections 36 and 37 supplement for investigational medicinal products, the guidance for reference and retention samples given in Annex 19.
• An additional note has been introduced to clarify the meaning of “reconstitution” as referred to in article 9.2 of Directive 2005/28/EC.
• The content of the Batch Certificate referred to in Art. 13(3) of Directive 2001/20/EC, agreed following a separate public consultation, has been added as an attachment.
• A few editorial changes have been made to sections not consulted upon in the interests of updating references and consistency with terminology used throughout the GMP Guide.
  
  

For a revised version of Annex 13 please click ‘more info...’.