2007 - Another Year of Success

New Clients

In 2007, in addition to supporting on-going clients, QED-QED has acquired 7 new clients in which support such as development of quality systems, auditing, MHRA inspection support and tailored made training were given.

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Support for U.K. Companies for MHRA Inpsections

QED-QED consultancy support was given to a U.S. generics company to help prepare and manage their first MHRA inspection. An "MHRA" style audit was performed by QED-QED, highlighting the different inspection tactics of an MHRA inpsector against an FDA investigator. This enabled the company to improve in various operational areas before the inspection. Support and assistance was also given during the inspection, leading to a successful outcome.

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GMP Training Courses

A number of GMP training courses including GMP Documentation, Technology Transfer, Supplier Management, and GMP for Senior Leaders have been developed and delivered to the industry with excellent feedback. The aim of combining technical content with behavioural aspects of each subject has been well received. QED-QED has ended the year with a very positive note on training with more to come in 2008.

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Countries Supported during 2007

QED-QED has worked with and supported companies in the following countries during 2007:

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Auditing Services

QED-QED has continued to provide an auditing service for companies within the bio/pharmaceutical industries. Audits were performed to support GMP and regulatory compliance at a number of companies in various countries. The consistent in-depth and pragmatic auditing approach employed by QED-QED has again, like previous years, resulted in very positive comments from our clients.

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Industry Associations and Colleagues

QED-QED has continued its association and membership with PharmaWisdom, a Kent-based network of companies with an international client list, who provide services to the global pharmaceutical and biotechnologies industries. Visit www.pharmawisdom.com for more information.

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2005 - A year in reflection

Support to U.S. Company for MHRA Inpsection

QED-QED consultancy support was given to a U.S. generics company to help prepare and manage their first MHRA inspection. An "MHRA" style audit was performed by QED-QED, highlighting the different inspection tactics of an MHRA inpsector against an FDA investigator. This enabled the company to improve in various operational areas before the inspection. Support and assistance was also given during the inspection , leading to a successful outcome.

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GMP Training Courses

A number of GMP training courses including GMP Documentation, Technology Transfer, Supplier Management, and GMP for Senior Leaders have been developed and delivered to the industry with excellent feedback. The aim of combining technical content with behavioural aspects of each subject has been well received. QED-QED has ended the year with a very positive note on training with more to come in 2006.

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Countries Supported during 2005

QED-QED has worked with and supported companies in the following countries during 2005:

Auditing Services

In 2005, QED-QED has undertaken over 30+ audits within the bio/pharmaceutical industries, supporting a range of companies from small start-ups, development companies to global internationals. Our in-depth evaluation of the facilities/process and pragmatic approach to potential issues has resulted in very positive comments from our clients.

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API Audits as A Result of New E.U. Legislation

In October 2005, Part 2 of the Orange Guide came into force defining the GMP requirements for API manufacturing. The E.U. legisation states that  GMP compliance status of API resides with the Marketing Authorisation Holders.

The introduction of this legislation has led to a significant increase in the number of API audits requested and performed within the industry. QED-QED has supported many companies by undertaking audits of API facilities. Our clients have acknowledged that audits performed by QED-QED have provided excellent value with full report detailing operations reviewed and observations given with respect to areas for GMP concerns and improvements.

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India

QED-QED has been busy supporting two Indian companies in achieving E.U. GMP compliance status of their facilities. Plans are in place for more similar projects in 2006.

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Qualified Person Support

QED-QED has supported a virtual company with their QP services.

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Industry Associations and Colleagues

PharmaWisdom was formed in 2005 with QED-QED as one of the founder members. PharmaWisdom is a new and expanding Kent-based network of companies with an international client list, who provide services to the global pharmaceutical and biotechnologies industries. Visit www.pharmawisdom.com for more information.

In 2005, QED-QED has also supported several Industry Associations on a number of projects through working parties, discussion forums, surveys and meetings. 

Several discussion articles have been written for Essential Science (www.essentialscience.co.uk), an industry colleague, as "food for thought". The same articles can be found under Brain Drain of the Month and Archived Articles.

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Web Changes

The QED-QED website has been renovated in the last quarter of 2005 and launched beginning of 2006 to be more user friendly.

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Qualified Person Release of IMP’s Imported from Outside of the EU: A Business Benefit?

In May 2004 EC Directive 2001/20/EC came into force, impacting the way clinical trials are controlled. This article focuses on one part of that directive, the duties of the Qualified Person (QP) when releasing product that has been manufactured outside of the E.U.  The directive requirements are as laid down in Article 13 of the directive. Annex 13 of Volume 4, Good Manufacturing Practices gives the QP a more detailed view of how to comply with the directive.

When a medicinal product destined for a clinical trial is manufactured outside of the E.U. the QP needs to establish that the facility and practices at that facility meets, as a minimum, the GMP requirements of the E.U. The QP also needs to ensure that each batch manufactured is assessed for compliance with the authorisation for the clinical trial. How is this best achieved?

Normally this would be done via an audit of the facility and then remote review of the batch documentation pertaining to individual batches. However, this is a simplistic view and the intricacies of how this is effectively achieved can provide some interesting debate. Some questions that might arise:

Who should audit? The QP? What if the QP is not an experienced auditor?

What if the audit, as is likely, raises compliance issues indicating that the facility is not in total compliance with E.U. GMP rules?

If the supply of product is to carry on over a period of time how often should an audit take place?

How does the QP deal with change within the supplier’s facility?

How does an MRA with the country involved affect the duties of the QP?

How much responsibility does the QP have for decisions made by the supplier on individual batch issues?

In the author’s opinion an audit and routine batch review is not enough to enable the QP to effectively carry out his/her duties. It is also not necessarily going to give the business benefit that could result from a more structured approach. The following is suggested as a competent, realistic and effective means of ensuring that the QP batch release adds real business benefit:

The QP must have personal knowledge of the facility and the key staff employed at that facility, essentially a sound working relationship should be developed and maintained. Where non-compliances are identified, the QP must risk assess the situation and be comfortable with the corrective action plan to address the non-conformance. This plan must be monitored. Where an MRA exists, Annex 13 indicates that the responsibility of the QP to control and have continuous knowledge of the activities within the facility is reduced. It is the author’s opinion that such personal knowledge of the facility, and detailed overview of their activities, is just as important. A Technical Agreement should be in place between the individual companies that, in particular, must give direction on how change is controlled between both companies and who is responsible for individual activities.

For individual batch review, the QP should not restrict his/her activities to the routine manufacturing and testing documentation. In particular, deviations and/or OOS reports must be thoroughly investigated. The transport conditions should also be considered and ‘Quality Systems’ information, such as audit reports, validation status, stability data and Annual Product Reviews should be available and referred to where appropriate.

The use of the QP for batch release can give real business benefit, if the procedures and practices developed enable a good working relationship between the individual parties and a review that readily establishes that the batches released not only meet the basic requirements of the directive, but also ensures that appropriate proactive activity is undertaken, leading to reduced issues, greater confidence and ultimately less risk to the clinical trial.

Alan Smith CChem, MRSC, PG(Dip)IPS

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The relevance of cGMP training for senior managers

How many senior managers have up-to-date cGMP training? If they do, how relevant was it to their day-to-day work?

Regular cGMP training, a mandatory requirement of the regulatory authorities and a basic important tool for those of us working in compliance with the GMP regulations within the bio/pharmaceutical and biotechnology industries. Yet as senior managers, how often have we undergone cGMP training sessions and come away gaining only an entry in our training records and little else? Indeed, we seem to get less out of cGMP training as we climb the corporate management ladder and yet we make important decisions routinely regarding GMP issues.

So why is it that cGMP training appears to be more relevant to “hands-on operational” staff than “desk-based” senior managers? In the author’s opinion, this is due largely to the fact that cGMP training courses are designed with practical learning and the target audience are typically working at operational levels where their jobs involve performing specific practical tasks (e.g. analysis of a product, operating a blister packer, cleaning of a granulation machine, completing batch records etc) using set instructions such as SOPs and protocols. For us senior managers, there are no standard manuals or training templates when it comes to communication and making decisions. These activities take up a large percentage of our job and we all do it differently because each one of us have a different management style. It is no wonder then that we often think of the standard GMP training as a tick in the box, because we have long past the days when we carry out practical tasks. That leaves us in a bit of a dilemma when it comes to cGMP training. We attend the training because it is mandatory but resent the time spent as an opportunity cost to getting some other work done.

It is the author’s opinion that relevant cGMP training is of paramount importance to senior managers, in particular those who do not work within Quality/Production/Engineering, because we make critical decisions with potential major impact on product quality and patient safety. FDA and MHRA guidelines require personnel to be trained so the question is not whether we need cGMP training but its relevance to our jobs. Without a doubt, any training will only benefit and improve performance when it is relevant. Well designed, developed and executed cGMP training specific to the senior managers’ needs (combined with maintaining up-to-date technical knowledge) will not only help us do our jobs more effectively but also that of our staff. Critical elements of any training and education should include an understanding and appreciation of each of our roles, in terms of how they interact with each other and how our actions can impact the organisation. Everyday decisions are made by senior managers, with little communication or thought to the GMP implications. Without a doubt, some of these decisions lead directly to product issues. The following are just a few of the author’s real experiences:

·     A seemingly simple decision made by Distribution to change a freight forwarder to reduce costs resulted in regulatory dossier complications.

·     Change of site of manufacture (the same supplying Company) of a glass vial agreed by Purchasing to improve the lead-time led to manufacturing/packaging issues for Japanese supply.

·     A computerised training management system purchased by HR for recording site-wide training gave rise to inspection observations for non-compliance to 21CFR part 11.

For senior managers, good cGMP means a thorough understanding of the different functionalities so that informed decisions can be made, which are communicated appropriately, to ensure the quality and GMP compliance status of the organisation is not compromised.

There is no question about the relevance of cGMP training for senior managers. The major stumbling block is the design and development of an appropriate training package to fulfil our needs and to make us more effective and informed managers………….

Alice Li CChem, MRSC, DMS, MRQA

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The Art of Preparing for Regulatory Inspections

Those of us who have worked within the pharmaceutical industry for a reasonable length of time would have been involved in FDA, MHRA, and various other regulatory inspections at sometime in some shape or form. For those of us coming out of it unscathed (and with a good result) then we can be excused for feeling pleased with ourselves. Why then does the notification of a forthcoming regulatory inspection still make our blood run cold?

The answer often is that we know there are non-compliances within our work place and we would rather not  “air our dirty linen” in public. Of course, Murphy’s Law will prevail and the inspector(s) will find them! We all have non-compliances that we know about and can be guilty of not doing enough to resolve them in a timely manner. This article is not about how to manage or resolve these issues but rather about how we can use the art of preparation to help influence a better inspection outcome. It is not the author’s intention to suggest that inspectors should be misled.

Preparing for a regulatory inspection is both science and art. Let’s compare it to a game of chess, not only do we need to know the rules of the game and the capabilities of each piece (this is the technical knowledge and is the science) but in order to get to “check mate” and win the game we need to have a strategy, to understand and appreciate the importance of the movements not only of each piece but collectively as a whole game (this is the art). Similarly, we can all be trained systematically about the structural aspects of an inspection, for example: observations, 483s, opening and closing meetings, warning letters etc (this is the science) but there is no hard and fast rules about the actual preparation. For example, the strategy on inspection core team (fronters and back room control) selection, control room layout, management of personnel/facility during an inspection etc (this is the art). Indeed how do you go about training someone to have a “nose for it”?

I have come across many companies spending a small fortune on the science part of inspection preparation but little attention on the art of inspection strategy and the selection of a brilliant core team. Often, core teams members are thrown together because of their availability or their job position rather than because of their aptitude and natural flair to host and manage inspections.

Personally, I believe a successful inspection outcome is influenced by the art of choosing the correct strategy and the right members for the inspection core team.

The strategy will largely depend on the objective(s) of the inspection (GMP, PAI, Quality Systems, For Cause etc) and it is of paramount importance to select the inspection core team members accordingly. The inspection core team must fully understand the company culture and objectives so that these can be integrated in the preparation. The members should be humble, graceful, assertive and yet knowledgeable about all the relevant issues. They need to understand and appreciate when/how to act, what with, why and with whom.

Apart from the art of getting the right strategy and inspection core team, there is the art of creating the right atmosphere during the inspection. This is not just in the inspection front room but the entire site. Imagine how the inspectors would feel coming out of the controlled calm of the front room only to be greeted by the panic experienced by all on their way to the wash room? Not to mention the stress levels of all the staff. A controlled and calm environment will influence a better final outcome compared to misunderstandings and errors caused by an atmosphere of panic.

Naturally, all wise men and women in the industry would know that preparing for regulatory inspections is an on-going art. However, art alone without current sound technical knowledge is not nearly enough to provide a successful outcome. Just like the balance between body and soul, ying and yang, the science and art should work to compliment each other.

For those of us who have somewhat failed in understanding the art, or achieving the science and got a less than desired inspection outcome, there is always a last resort……..the art of praying!

Alice Li CChem, MRSC, DMS, MRQA

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Management of Mix Up Prevention: Reality or Myth?

One of the most common causes of recall, and also a frequent GMP failure, is where material from one batch of product is inadvertently mixed with a different batch of either the same product or a different product. This might range from a single tablet found on a packaging line, to a drum of excipient labelled as a different material. Many companies involved in GxP activities have a ‘mix up prevention’ programme, either running as a defined project, or as an ongoing part of the business.

But where does mix-up prevention start and end? In the author’s opinion it starts not in manufacturing, nor in packaging, nor in the warehouse, nor in the goods received area. It starts with design. Design of your manufacturing facility and the equipment employed. The layout of a facility, to facilitate good material flow can be extremely successful in preventing mix-ups, for instance. The use of equipment that is easy to clean and check that it is clean will also reap real benefits. It also starts with the design of your product (should we use a blister pack, should the ampoule have coded markings, should this tablet be white?).  And what does mix-up prevention include? As well as the obvious areas of manufacturing, packing, and warehousing, it also includes fundamental systems, such as training, supplier selection and approval, documentation design, maintenance programmes, artwork control…. And it never ends, as continuing to manage performance criteria, changes within the facility, continuous improvement initiatives, new products, audits, self inspection… all bring fresh data and new challenges…In short, mix up prevention touches every aspect of the business and is a continuous process. It is not something that can be ‘flavour of the month’. It must be something that is a key part of your business. It is vitally important to keep mix up prevention as a high profile activity. 

How do we therefore ‘Manage’ mix up prevention? The key is to risk assess the operation, by reviewing the history of mix-ups and by reviewing the status of all areas of your operation, including design, system and operational aspects. The programme should then prioritise the higher risk areas, which are reasonably practical to improve. It may not be possible to re-design your facility, but if the processes employed can be improved, or if simple design improvements, such as the lighting in an area, can be enhanced, then fewer mix-ups should result. The profile of mix up prevention must always be high. ‘Visual Factory’ style techniques are extremely powerful for maintaining that visibility.

One of the major areas for concern is the packaging floor and packaging equipment. The author has been involved in a global programme concentrating on this aspect of mix up prevention and it is amazing that simple improvements (often highlighted by the operational staff involved) to older facilities can reap real benefits, not only in GMP, but also in staff morale. On one packaging line several simple changes, costing less than a few thousand pounds sterling, made a tremendous improvement to the operation of that line.

Of course, there are also some obvious areas, which require continual monitoring. How many times have you seen two different batches of the same product/material being stored next to each other, with inadequate security/packaging. Bulk unlabelled vials in unlocked, open containers is a common audit finding and the transportation of such materials around a manufacturing site is often found as the root cause during failure investigations of mix-ups. 

Mix-Up prevention is a reality, it can be successfully managed and if successfully implemented and maintained, will lead to improved GMP, less recalls and most importantly, greater patient safety.

Alan Smith CChem, MRSC, PG(Dip)IPS

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Control of cGMP Documentation after Plant Closure

An essential element of any GMP Quality System is the management of documentation, be it in electronic or hard copy format. Documentation management may be defined as the system of controlling both paper-based and electronic information from its creation to its archival and eventual destruction.

At first glance this may seem a relatively trivial task and, whilst many companies have specialised departments working to defined systems for dealing with this activity, most will require to set up specific systems if a plant or site is to be closed. Such plant closures are, unfortunately, a common activity and regulatory authorities will perform specific inspections to ensure that, following closure, documentation and the history of activity that occurred at the plant is maintained and available, remember that batches may be on the market for up to five years following a closure. Essentially, following closure, there must be a ‘controlling company’ identified that is accountable for the documentation and the batches which remain on the market.

Companies are obliged to keep certain records for predetermined periods of time for legal purposes. Batch documentation is normally kept for the shelf life of the batch plus one year, however, other documents, such as validation reports, need to be kept for far longer. These records are primarily kept for the purposes of being able to investigate complaints, adverse events and to aid investigations into potential recalls. If a recall is required, then records must be available to be able to trace the product involved and contact the appropriate distributors/hospitals/pharmacies.

When faced with a plant closure, companies have the following principal choices:

Of course, it is not just the document management/retrieval that is required, there must be the ability to review such documentation, investigate and root cause any issues, make a decision on involved batches and execute any action required.

In the author’s experience, the establishment of a third party contract, ideally involving staff from the closing site, in managing not just the documentation but also any complaints or regulatory questions that may arise, provides an excellent solution. Such a third party must, of course, have a technical as well as legal contract, which defines the services to be provided. It must also be audited on a regular basis and the communication between the two companies firmly defined and established.

If the paper copy were the only existing copy it would normally be advantageous to duplicate an electronic backup by scanning the paperwork. Not only does this make the information more accessible for day-to-day use, but it also provides a method to recover the information should the original documents be lost. For GMP purposes, unless the duplication process is fully validated, then the original copy would remain as the legal copy.

If the documentation is to be stored at a specialised storage company, separate to the company or department that will perform any investigations, it is important to also audit that company carefully to ensure storage of GMP documentation will meet regulatory requirements. The documents must be kept in a secure and controlled environment. For very long-term storage of old documents, companies that offer temperature and humidity regulated conditions should be found, although their charges will usually be significantly higher. A service level agreement with the company is essential, detailing working hours and retrieval times.

Depending on the type of document, the method of getting the document back is important. If the paper document is to leave the store to be sent elsewhere, how is it managed? The best solution, if possible, is to have a copy of the document scanned, faxed, or e-mailed back so that the original never has to leave the storage facility. If the originals are required a securely controlled system for signing the documents in and out is critical.

Finally, the controlling company should have a focal person, who is in regular contact with the contractor(s) dealing with the documentation from the closed site. This will ensure an effective means of continuing to remain compliant after a site closes.

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January 2005 - Launch of PharmaWisdom

PharmaWisdom is a new and expanding Kent-based network of companies with an international client list, who provide services to the global pharmaceutical and biotechnology industries.

Meeting your needs by providing:

►      One reference point for high quality flexible suppliers.

►      A group that works together to provide bespoke solutions to our customers’ needs.

►      Extensive experience. All member companies have staff with decades of experience working within their areas of speciality.

►      Confidence. All companies have been vetted by the group to ensure they have the relevant experience and quality standards in their areas(s) of expertise* which saves your company time and money when searching for service solutions.

►      Strictly confidential dealings between you and any group company.

►      A group complaints procedure to ensure that standards stay high.

Existing members:

All companies have a culture of delivering a high quality of service and quality assurance, making the management of outsourced work a much simpler task.  

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