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?

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/).

Mit QbD und PAT die Qualitätskontrolle signifikant verbessern

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Das Konzept des Quality by Design (QbD) zusammen mit den technischen Möglichkeiten der Process Analytical Technology (PAT) erlauben

ein besseres und rascheres Verständnis von Herstellungsprozessen pharmazeutischer Produkte.

Eine Freigabe mittels Real Time Release (RTR) beschleunigt die Freigabe. Mittels eines  risikobasierten Ansatzes auf wissenschaftlicher und technischer Grundlage können so Entwicklungs-, Herstellungs- und Qualitätssicherungsprozesse sowohl für Hersteller wie auch Überwachungsbehörden optimiert werden. Selbst die Sicherheit für den Patienten ist erhöht und eine Kostensenkung für das Gesundheitssystem erzielbar. Die technischen Voraussetzungen sind geschaffen. Regulatorische Vorgaben befinden sich entsprechend im Wandel. Die pharmazeutische Industrie ist gefragt die existenten Möglichkeiten zu nutzen. So lassen sich ständige Produktionsverbesserungen innerhalb des zuvor definierten Design Space ohne Änderungsmeldung umsetzen.

Ein besseres und sichereres Produkt sind das Resultat.

Zögern Sie also nicht, die Einführung des QbD Konzeptes vorzunehmen. Der temporär erhöhte Zeitaufwand zur Einarbeitung darf kein Hindernis mehr sein in Zeiten der steigenden Angebote externer, fachlicher Expertise (siehe beispielsweise www.pharmoveo.de).

The Invention of the Electron Microscope

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The invention

The development of the electron microscope (EM) was based on the discovery that a magnet coil may function as an optical lens. After having shown in his thesis of 1929 that sharp and magnified images of electron-irradiated hole apertures could be obtained with the short coil, Ernst Ruska was now interested in finding out if such images could be further magnified by arranging a second imaging stage behind the first stage. Such an apparatus with two short coils was easily put together. In April 1931 Ruska obtained the definite proof that it was possible. This apparatus is justifiably regarded today as the first electron microscope even though its total magnification of 3.6 x 4.8 = 14.4 was extremely modest.

The type of microscope designed by Ruska is called transmission electron microscope. The electron beam passes through the specimen being observed that must be sufficiently thin. The resolution of EMs is considerably higher than the resolution of light microscopes since the wavelength of the used electron beams is 10,000 times lower than that of light. Conventional light microscopes have a resolution of about 4,000 Å (1 Å, Angström = 10-8 cm), whereas EM resolution averages 1 Å.

Ruska left the university to pursue his research in the field of electron optics in industry and joined Siemens & Halske, where he developed an electron microscope together with Dr. Bodo von Borries. This serially produced EM was put on the market in 1939. Ruska considerably improved the research tool over the years. In 1986 he was awarded the Nobel Prize in Physics together with Dr. Gerd Binning and Dr. Heinrich Rohrer.

 Ernst Ruska once said that “… occasionally it can be more a matter of luck than of superior intellectual vigour to find a better – or perhaps the only acceptable way”. It maybe that one or the other research performed in Your lab contains inventive steps? Support with respect to pharmaceutical patent inventions one will find at www.pharmoveo.de.

Biography

Ernst Ruska was born 1906 in Heidelberg, Germany. He is the son of a professor. In 1925, Ruska took up studies in electrical engineering in Munich, which he pursued in Berlin two years later. From 1928, his studies at the Hochspannungsinstitut (institute of high voltage technology) focused on high voltage and vacuum technology. At that time, he discovered the basic principle of electron microscopy. He joined a project group headed by Dr. Max Knoll. This group built the first functioning electron microscope in 1931. For the first time, sharp images were obtained by means of electron beams. In 1933, pole shoe lenses developed in cooperation with Dr. Knoll allowed to obtain the first images magnified 12,000 times, surpassing the resolution capacity of the light microscope. In the same year he gained his doctorate. From 1949 to 1971 he gave lectures at the Freie Universität and Technische Universität of Berlin. In 1955, he left Siemens & Halske AG to become Director at the Institut für Elektronenmikroskopie (institute for electron microscopy) of today’s Fritz-Haber-Institut of Max-Planck-Gesellschaft. Prof. Dr. Ing. Dr. h.c. mult. Ernst Ruska died in Berlin 1988.

There is a website on his person with more detailled information e.g. the text of his nobel lecture. There is also a book published on his memoires. More information on the inventions he made can also be found on the website of the German Patent and Trademark Office.

 

Does the shortage of skilled employees also hinder growth within the pharmaceutial industry?

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The health care industry is in good shape. The main reasons for that are the generally positiv economic develoment and the growing awareness of a healthy life style within the general public. This has a positive effect on the demographical change. Therefore this sector is still the driving force in the employment development within Germany.

After tough years in 2008 and 2009 the German pharmaceutical industry looks at a continuously positive economic trend since 2010. This positiv trend is also reflected in the investment plans of companies.

 

Negative impacts however which need to be controlled in the future are:

1. economical political decisions e.g. how to control the national debt within Germany as well as in the EU

2. the development of prices for energy and raw materials

3. growing expenditures on wages e.g. due to increasing numbers of full time employees (FTE)

4. shortage of skilled employees e.g. in Germany 43 percent of all companies within the health care industry consider this already a significant business risk for 2012.

 

To maintain the necessary amount of skilled employees at the company gains more and more significance.

One possibility companies rely on is to increase the overall amount of  people being educated within the company. 

Another strategy is to establish processes in order to maintain the employability of the existing staff. 

Health preventing activities are offered.

Concepts are desigened to allow for a better work life balance.

More often the expertise of specialists working as freelancers is used in order to reduce the work load in peak periods and to prevent the existing full time employees from burnout situations. One example on how specialized freelance activities can be requested these days can be seen at www.pharmove.com