Technical transfer of testing methods – new guideline

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The European Commission (EC) has released the draft revision for its good manufacturing practice (GMP) guideline—chapter 6 Quality Control including a new section addressing the technical transfer of testing methods and other items including out-of-specification results.

 A public consultation was launched earlier this year with comments due on 18 July 2013. The EC stated that these revisions were needed to reflect the latest thinking relating to best practices.

 

Chapter 6 Quality Control:

IN SUMMARY The chapter states that test methods should be verified to ensure that they are the same as those validated in the original marketing authorisation dossier. Technology transfer between testing facilities must be documented and tested to ensure that 1) it is the same technology, 2) operators are adequately trained, 3) standards are maintained and 4) acceptance criteria is established.

IN DETAIL Technical transfer of testing methods

6.37   Prior to transferring a test method, the transferring site should verify that the test method(s) comply with those as described in the Marketing Authorisation or the relevant technical dossier.  The original validation of the test method(s) should be reviewed to ensure compliance with current ICH/VICH requirements.  A gap analysis should be performed and documented to identify any supplementary validation that should be performed, prior to commencing the technical transfer process.

6.38   The transfer of test methodology from one laboratory (transferring laboratory) to another laboratory (receiving laboratory) should be described in a written protocol.

6.39   The protocol should include, but not be limited to, the following parameters:

  • identification of the relevant test method(s) undergoing transfer
  • Identification of the additional training requirements
  • identification of standards and samples to be tested by both laboratories
  • identification of any special transport and storage conditions of test items
  • identification of the testing to be performed
  • the acceptance criteria which should be based upon the current validation study of the methodology and with respect to ICH/VICH requirements

6.40   Deviations from the protocol should be investigated prior to closure of the technical transfer process.  The technical transfer report should document the comparative outcome of the process and should identify areas requiring further test method revalidation, if applicable.

6.41     Where appropriate, specific requirements described in others European Guidelines, should be addressed for the transfer of particular testing methods (e.g Near Infrared Spectroscopy).

 

 

Additional drafts that were released at the same time are good manufacturing practice (GMP) guidelines—chapters 3, 5 and 8. Comments are as well due on 18 July 2013.

The proposed changes, also available at the EC’s website, are summarised below:

Chapter 3 Premises and Equipment: Section 6 has been revised to address the prevention of cross-contamination in facilities that manufacture multiple products lines. This topic is also addressed in chapter 5. Manufacturers are advised to follow quality-risk-management principles to assess and control all present or inherent risks in the facility.

Reference is made to a new complementary guidance on toxicological assessments relative to setting carryover limits in shared facilities and equipment. The chapter states that risk assessment should include among other parameters a toxicological evaluation of the products being manufactured.

In cases where cross-contamination cannot be adequately controlled by operational or technical measures, the facility will not be allowed to manufacture multiple product lines. The same applies to cases where scientific data does not support threshold values or if threshold values are too difficult to detect.

Chapter 5 Production: The chapter contains several new revisions, including refined guidance on where products should and should not be manufactured (i.e., not in the presence of non-medical products) and the use of technical poisons like pesticides or herbicides (which should not be used in the presence of medical products). Revisions of sections 17–20 are intended to address cross-contamination and refer to toxicological assessment guidance.

Sections 26–28 on the qualification of supplies have been revised to reflect the legal obligation of manufacturing authorisation holders to ensure that active substances are produced in accordance with GMP. The changes also address supply chain traceability in agreement with requirements set out in the 2011 Falsified Medicines Directive.

The chapter states that supporting evidence for each supplier/material approval should be maintained. Staff involved in these activities should have a current knowledge of the suppliers, the supply chain and the associated risks involved. Where possible, starting materials should be purchased directly from the manufacturer of the starting material.

This requirement applies to APIs and excipients which are considered to pose a particular risk to the quality of the medicinal product, as explained in the chapter. All starting materials used in the production of medicines should be tested, as should the finished product.

Section 33 has been incorporated to provide clarification on the testing of starting materials as well as to harmonise expectations of manufacturers in this aspect. Section 68 introduces guidance on notification of regulatory authorities of potential drug shortages.

Chapter 8 Complaints, Quality Defects and Product Recalls: Changes have been made to incorporate quality-risk-management principles when investigating quality defects/complaints and when making decisions on product recalls or other risk-mitigating actions; to stress on the need to determine the cause(s) of quality defects/complaints so that necessary actions can be put in place to prevent or minimise recurrence; and to clarify expectations and responsibilities regarding the investigation and reporting of quality defects/complaints to the proper authority.

Risk Evaluation of pharmaceutical excipients

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The EU Commission has issued Guidelines for the risk evaluation of pharmaceutical excipients for consultation until April 30th 2013  – fulfilling the request from the Directive 2011/83/EC, Article 47 which says:

“The principles of good manufacturing practice for active substances used as starting materials referred to in point (f) of Article 46 shall be adopted in the form of detailed guidelines.”

The three Guidelines with the titles

  • Determination of appropriate GMP based on type of excipient 
  • Determination of Excipient Manufacturer’s Risk Profile 
  • Confirmation of Application of Appropriate GMP

were not issued separately, but are comprised in one document entitled “Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use”.

The first Guideline “Determination of appropriate GMP based on type of excipients” initially refers on the ICH Q9 Guide “Quality Risk Management” incorporated in Part III of the EU GMP Guide. The quality risk management principles described there are also to be applied to pharmaceutical excipients. In addition the new Guideline contains specific criteria for the risk evaluation in regard to

  • The origin of the excipient 
  • The dosage form and use of the medicinal product in which it is used

Finally the Guideline lists a number of GMP principles that have to be followed by the excipient manufacturer at minimum.

The second Guideline “Determination of Excipient Manufacturer’s Risk Profile” requires the creation of a weak point analysis based on data e.g. from audits at the API manufacturer. It also has to be considered whether the excipient manufacturer is accredited or whether his QM system is certified. Based on the risk profile determined an appropriate control strategy has to be established.

The last Guideline “Confirmation of Application of Appropriate GMP” requires a permanent examination of the excipient’s and manufacturer’s risk profile. For that purpose the Guideline provides the following 5 observation criteria:

  • Number of quality defects in excipient batches 
  • Type and severity of the defects 
  • Loss of accreditation at the excipient manufacturer 
  • Trends at the quality attributes of the medicinal product (depending on nature and role of the excipient in the dosage form) 
  • Audit (re-Audit) at the excipient manufacturer

The document “Guidelines on the formalised risk assessment…” with the Guideline drafts is available on the EU Commission’s News site of the EU Commission – open for consultation until 30 April 2013. Here you will get directly to the document: http://ec.europa.eu/health/files/gmp/2013-02_guidelines_excipients_cons.pdf.

The implementation of the new requirements will be covered e.g. at an ECA training course on GMP and GDP for Pharmaceutical Excipients in Prague, October 15th-16th,2013.

Shareconomy – sharing knowledge increases knowledge

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Knowledge is the most important resource of the information age. It is a hard-hitting competitive factor in an era when new knowledge keeps overtaking the old at an ever-more rapid pace. It is therefore crucial for companies to exploit their know-how and competencies as thoroughly as possible.

Sharing platforms have already demonstrated their value in innovative companies, enabling staff to exchange information across department boundaries. As they do so, this social communication promotes the formation of powerful teams benefiting from individuals’ bundled professional knowledge. The communication also facilitates searches for in-house specialists who can quickly explain difficult matters. Micro-blogging and instant-messaging services target a project’s participants and distribute information to them quickly. Forums also serve as platforms for fast and unbureaucratic discussions of internal processes, problems and potential improvements.

In addition, these approaches to sharing can create transparency within the company. This is because employees often work parallel to one another on similar issues. A more broadly based access to content – e.g. to analyses, proposals or customer reports – saves time while boosting efficiency. Centrally accessible blogs, wikis and FAQs are a channel making employees’ specialized knowledge accessible to a wider group. These solutions become essential if a responsible party’s departure would result in the loss of knowledge.

The scenarios for knowledge-sharing and participation are not immobile at all. Field representatives benefit from access to a centralized pool of knowledge. They can call up company information during their field work, such as visits to the clients, and use it purposefully in their dealings with them.

Even beyond the limits of the company, the shareconomy has become a critical factor for success. For example, there is a demand for elements that integrate suppliers and customers into internal processes. This especially applies to intercompany cooperation and research projects with universities. Information technologies play an increasingly important role in a growing number of industry sectors, including plant engineering and logistics.  Social Media can be used to easily integrate external partner, consultants, supplier and customer into your companies processes (Prof. Dieter Kempf, DATEV eG, #01-2013 www.B4BMITTELSTAND.DE).

After “Cloud Technology” in 2011 and “Managing Trust” in 2012, “Shareconomy” is the keynote theme for CeBIT 2013. Cloud-based applications are clearly on the rise, and have now earned user trust. Successful companies benefit from the expertise of their partners and thus increase their odds of success – since knowledge is the resource that you increase by sharing. How does Your company share knowledge?

The utility model – das Gebrauchsmuster – application strategies

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You can apply  to postpone the publication of a utility model (Antrag auf Aussetzung). Doing so you can decide at which timepoint to register your utility model. This can be either directly after filing the application or at an individually choosen later point in time until the expiration of a period of 15 months beginning either with the day of filing the application or the priority date (Sec. 8 (1) Utility Model Law, Sec. 49 (2) Patent Law).

ADVANTAGES: Postponement may be useful if the applicant intends to

1. file an application in non-member States of the Paris Convention for the Protection of Industrial Property, 

2. make preparations in view of the commercial exploitation of the invention

3. wait for the result of a search before the registration of the utility model. The request for ascertainment of publications (search request) may be submitted at the time of filing the application, but also at a later date.

IMPORTANT TO KNOW: No industrial property right arises prior to registration. You can withdraw your request on postponement at any time.

 

For filing a utility model in Germany you must use request form G 6003 issued by the German Patent and Trade Mark Office. Together with the request, you must furnish a technical description of the invention. Furthermore you must submit claims. You can – but need not – enclose drawings showing details of your invention.

For more detailed information please read the brochure Information for Utility Model Applicants (http://www.dpma.de/docs/service/formulare_eng/gebrauchsmuster_eng/g6181_1.pdf).

 

Gesunde Arbeit – Wege aus der Tretmühle

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Der Stress im Job steigt. Wie damit umgehen? Wie sieht gesunde Arbeit aus?

Eine Aufgabe nach der anderen Erledigen – Telefon und EMail im Block abarbeiten. Bei komplexen Aufgaben 50-55 Minuten arbeiten, 5-10 Minuten pausieren mit Bewegung und frischer Luft. Bei körperlicher Arbeit auf den eigenen Körper hören. Das Gehirn baut ab, wenn Arbeit monoton ist – Angebot unterschiedlicher Tätigkeiten führt zum Effizienzerhalt ebenso wie Erfolg und positives Feedback.

Gesunde Arbeit ist Arbeit, bei der viel soziale Unterstützung, Wertschätzung und Handlungsspielraum vorhanden sind und Leistungsdruck vermieden wird sagt Michael Kastner, Professor für Organisationpsychologie and der Universität Heidelberg, Institut für Arbeitspsychologie und Arbeitsmedizin.

Was nützt beispielsweise die perfekte Zeitplanung im Büro, wenn Ihre Beziehung zur Arbeit nicht auch geklärt ist? Was helfen wirksame Entspannungs-Rituale, wenn die Beziehungen zu den Familien-Mitgliedern unentspannt sind und hier Stress entsteht? Und was helfen die ausgeklügelsten Stressmanagement-Strategien, wenn ihnen unklar ist, welche Lebensziele damit erreicht werden sollen?

Wenn Sie auf irgendeiner Stufe Ihrer Lebenspyramide mit dem Vereinfachen beginnen, hat das Auswirkungen auf alle anderen Ebenen. Deswegen tut es so gut, einen überfüllten Kleiderschrank oder ein chaotisches Büro auszumisten… (Werner Tiki Küstenmacher, simplify your life-Autor)

 

8. Spiritualität:
über das eigene Leben hinausdenken, Sinn erleben

7. Sie selbst:
sich enträtseln, Lebensziel entdecken, entstressen

 

6. Partnerschaft:
entfalten, entfesseln, entstressen

5. Beziehungen:
entinseln, entfesseln, entstressen

 

4. Gesundheit:
entspannen, entschlacken, entstressen

3. Zeit:
entschleunigen, entperfektionieren, entstressen

 

2. Geld:
entschulden, entzaubern

 

1. Sachen:
entrümpeln, entstapeln

Innovations in Healthcare – Creating greater value

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Once upon a time in the world of healthcare, the only competition for a pharmaceutical company was other pharmaceutical companies.

Times have changed. Pharma companies are now competing with many nontraditional players in the healthcare arena, including electronic and mobile health firms, retailers, financial services companies and IT firms. Healthcare is no longer about just making a new medicine, but about

creating greater value for patients, providers and payers, and encouraging a more active and healthy lifestyle!

We often talk about manufacturing innovations, such as new dosage forms or more efficient manufacturing techniques, but let’s have a look at some of the innovations that have been made in the healthcare industry as a whole.

Microchips

A recent report from PricewaterhouseCoopers explained that microchips are being developed that will enable doctors to tell whether patients are taking their prescribed medicines. Nonadherence is a serious issue because it increases healthcare costs, increases patient deaths and belittles pharma manufacturers and scientists who have spent years developing a new drug or treatment.

Earlier this year, biomedical company Proteus Biomedical partnered with Lloyds Pharmacy to launch edible microchips. Data from the chips could be sent to phones (such as those belonging to doctors or a patient’s relatives) using Bluetooth technology.

Other companies are also pursuing similar technologies. PricewaterhouseCoopers further added that other implants in the pipeline include devices capable of injecting drugs at prespecified times.

Mobile health

A 2012 study has shown that 75% of the world’s population have access to a mobile phone, which means there is an enormous market for remote diagnostic tools and healthcare related apps. Indeed, many pharmaceutical companies (and other nontraditional companies) have launched apps designed to aid disease management or to enable remote monitoring.

According to PricewaterhouseCoopers, the app store Heppatique has launched a pilot programme that enables doctors to prescribe certain apps as part of a healthcare package.

Interestingly, mobile phones are also being used by pharmaceutical manufacturers, for example, to easily access protocols or guidelines, or to remotely monitor certain systems and equipment.

Video games

In the eighties video games were about plumbers jumping on turtles and blue hedgehogs running as fast as recklessly possible. Now, video games are being developed to encourage people to live more healthy lives, such as games that involve physical exercise. These games don’t just target patients, but everyone, and are blurring the boundary between healthcare and entertainment, as titles about keeping fit and exercise continue to emerge and top the gaming charts. Nintendo’s popular exercise game Wii Fit has even been incorporated into hospital physiotherapy programmes.

Video games are also being used in other ways. According to PricewaterhouseCoopers, HopeLab, a nonprofit organisation that aims to use technology to improve the health of children, has launched a video game designed to foster a positive attitude in young cancer patients. In the game, Re-Mission, players pilot a nanobot that travels through the body, destroying cancer cells, fighting infection and managing side effects from cancer treatments. HopeLab is also working on a new project targeting obesity. The project involves rewarding children for physical activity.

Pharmaceutical companies are also acknowledging the power and influence of video games. In 2010, Bayer unveiled a blood glucose meter in the US that connected to Nintendo DS and DS Lite consoles. Players receive points for testing blood sugar levels and meeting blood-glucose targets, which can then be used to unlock different levels in video games online.

New medicines are always going to be in demand, but while pharma companies are focusing efforts on drugs to treat lifestyle diseases, such as diabetes, obesity and high-blood pressure, and with drug development taking around 10 years, could companies find themselves outdone by other competitors seeking to make consumers healthy enough to avoid medication?

Continuous Wet Granulation – a positive case study

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Continuous manufacturing is now becoming a trend as its advantages are being increasingly recognized. At the PDA/EMA joint conference, which took place early December 2012, Martin Wunderlich from F. Hoffmann-La Roche presented an industry case study on solid drug product manufacturing based on this concept. He explained how a continuous wet granulation process for one of the company’s product (referred to as ‘product X’ hereafter) was developed using a quality-by-design (QbD) approach and a control strategy based on process analytical technology (PAT), as well as the technical challenges involved in the development of the process.

Continuous wet granulation offers significant advantages in terms of the general working principles and a straightforward scale-up

versus batch manufacturing, says Wunderlich. In this example, product residence in the granulator was less than 10 seconds with continuous wet granulation compared with batch manufacturing, which took 15 to 30 minutes for the granulation of the entire batch of product X. More importantly, in continuous wet granulation, each subfraction of the batch was subjected to the same processing conditions, providing a steady state for the vast majority of processing, including the start-up and shut-down phases, whereas for batch granulation, one has to question whether the shear energy and granulation liquid distribution were even throughout the entire batch. For the same reason, scale-up effects are difficult to predict for batch granulation because the dramatic changes in equipment surface area and volume would mean that the product experiences different conditions in both small and large scales. In contrast, time scaling occurs under identical process conditions for small to very large batches in continuous wet granulation and the same equipment is used for both development and commercial manufacturing.

 

 

 

Several key drivers that led to the adoption of continuous manufacturing at Roche were highlighted, for example,

process control was enhanced, apart from the

reduction in development time and cost, to name a few. Continuous manufacturing also

facilitated scale-up and offered

high flexibility through variable batch size.

The company’s experience with the process development of continuous wet granulation for product X demonstrated that a comprehensive process understanding could be achieved in a short time despite its challenges, such as the

need for more complex equipment design and controls, as well as the

professional data management system required for the various process controls and PAT tools.

Data presented by the speaker showed that both continuous and batch processes resulted in similar product quality with comparable in vitro performance.

Open Evaluation: about the future of scientific publications

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A scientific publication system needs to provide two basic services: access and evaluation.

The traditional publication system restricts the access to papers by requiring payment, and it restricts the evaluation of papers by relying on just 2-4 pre-publication peer reviews and by keeping the reviews secret. As a result, the current system suffers from a lack of quality and transparency of the peer-review evaluation process, and the only immediately available indication of a new paper’s quality is the prestige of the journal it appeared in states Nikolaus Kriegeskorte, a brain scientist from the Univeristy of Cambridge.

What are the options?

While open access (OA) is becoming a reality, Nikolaus Kriegeskorte promotes the establishment of open evaluations (OE). Evaluation steers the attention of the scientific community and thus the very course of science. It also influences the use of scientific findings in public policy.

An open evaluation (OE) system is pursued, in which papers are evaluated post-publication in an ongoing fashion by means of open peer review and rating.

Through signed ratings and reviews, scientists steer the attention of their field and build their reputation. Reviewers are motivated to be objective, because low-quality or self-serving signed evaluations will negatively impact their reputation. A core feature of this proposal is a division of powers between the accumulation of evaluative evidence and the analysis of this evidence by paper evaluation functions (PEFs). PEFs can be freely defined by individuals or groups (e.g., scientific societies) and provide a plurality of perspectives on the scientific literature. Simple PEFs will use averages of ratings, weighting reviewers (e.g., by H-index), and rating scales (e.g., by relevance to a decision process) in different ways. Complex PEFs will use advanced statistical techniques to infer the quality of a paper. Papers with initially promising ratings will be more deeply evaluated. The continual refinement of PEFs in response to attempts by individuals to influence evaluations in their own favor will make the system ungameable. OA and OE together have the power to revolutionize scientific publishing and usher in a new culture of transparency, constructive criticism, and collaboration.

In the area of pharmaceutical publishing the open access journal Results in Pharma Sciences (Elsevier) is going a first step having established PeerChoice.  A select group of reviewers choose actively the manuscripts they want to review from the abstracts of submitted manuscripts. However it is not open to everyone and ,as with traditional systems, the information is kept secure throughout the peer review process.

If You want to learn more about open evaluations visit the following Blog: “the future of scientific publishing” (http://futureofscipub.wordpress.com/).

Performance Management

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According to the calculation of independent institutes the reduction or loss of performance of employees does cost the overall economy 100 billion Euros, around 80 billion GBP, each year. This is a significant cost factor for a company’s rate of return. On average companies have to invest one complete additional annual salary to substitute the absence of one executive manager. As the German center of performance management describes in its seminars this does not necessarily need to be that way. With simplest methods and without too much effort loss of performance and Burnout syndroms can be avoided.

There are possibilities to avoid the described conditions. They will prevent high costs in case of absence of employees due to medical conditions. Therefore it should be in the interest of every company to implement a stringent Burnout prevention system. Unfortunately so far standardized concepts for performance management are missing.

The mission of the first German center for performance management and Burnout preventiontherefore is to achive such standardized concepts. 

Stress reduction in only ten minutes

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To relax during the day is sometimes difficult to achieve. The invest of ten minutes can help to significantly reduce the stress level and prevent from long term problems that continuous stress creates. In the following four fast and easy to realize tricks are described to help reduce the level of stress during every day life.

1. Create your space for relaxation

A space where you can go to and where there is no noise. A room, a corner or a bench in the park where you can go during lunch time. Try to be there every day for ten minutes. Never let any work, telephone or other job disturb you here. Anything that destroys should be avoided.

2. Be nice

If stress seems to overwhelm you try to do something nice for someone else. Buy a greeting card for a friend. Write a thank you note for a colleague who has helped you at work.

3. Recreation

During physical activities endorphins are released. Positive energy will be created. Walking, running, bicycling – many different types of sports will fit in ten minutes.

4. Mental activity

Is your mind circling around something unpleasant try to concentrate for ten minutes on a new mental challenge. Multiple studies show that people who maintain their mental activity live more intensive as well as more productive. Solve a crossword puzzle, a Sudoku or another mind game. You will prevent early aging of your brain.