european INDUSTRIAL
PHARMACY features 4
SEVERE DRUG SHORTAGES – WHO’S TO BLAME? What happens to the patient when quality oversight is deficient at many levels. by Michael Anisfeld
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GI TRACT CHALLENGES The GI tract forms a challenging obstacle course for medicines. It is therefore important to understand the factors that can affect drug release. by Emma L McConnell, Hywel D Williams and Samuel R Pygall
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STABILITY OF OMEPRAZOLE ORAL PREPARATIONS This study revealed a defect in the dissolution of an omeprazole product that led to its reformulation and a revision of the British Pharmacopoeia's dissolution test. by MG Lee, AJ Charvill, S Young, HL Douglas and S Matumo
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THE SAFETY OF EXCIPIENTS USED IN MEDICINES FOR CHILDREN A key consideration for those formulating paediatric medicines. by Jennifer Walsh
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SURVEY OF PHARMACEUTICAL EDUCATION IN EUROPE PHARMINE -- Report on the integration of the industry component in pharmacy education and training. by Jeffrey Atkinson, Jane Nicholson and Bart Rombaut
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BOOK REVIEW Quality in the manufacture of medicines and other healthcare products. reviewed by Dave Sharma
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EDITORIAL COMMENT
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REGULATORY REVIEW
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NEWS FROM THE EIPG
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EVENTS
ISSUE 13
• JUNE 2012
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associate editors
european
INDUSTRIAL
PHARMACY
Belgium: Philippe Bollen
Issue 13 June 2012 Bulgaria: Valentina Belcheva
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EDITOR Joe Ridge, MRPharmS
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european INDUSTRIAL PHARMACY is the official publication of the European Industrial Pharmacists Group (Groupement des Pharmaciens de l’Industrie en Europe) www.eipg.eu
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EDITORIAL BOARD Michael Anisfeld Alexander Florence Michael Gamlen Linda Hakes John Jolley
© 2012 Euromed Communications Ltd
Cover picture: Illustration of the gastrointestinal tract. (See pages 7-9) Image: Fotolia
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• Issue 13
editorial Dear Colleagues I would like to welcome you to the June edition of the European Industrial Pharmacy journal, which is sponsored by the European Industrial Pharmacists Group (www.eipg.eu). I have recently returned from our General Assembly meeting in Lisbon which was hosted by the Ordem dos Farmaceuticos and I would like to thank the following individuals from Portugal who made this meeting such a success, namely Nuno Moreira, President of Industrial Pharmacists Board and both Luís Rhodes Baião, Pharmacist, International Affairs and Joaquina Borges, Administrative Support and Logistics who work for the Ordem dos Farmaceuticos. I would also like to thank our guests whose contribution to the meeting was vital to its success and which allowed for constructive debate and the implementation of our strategic plan. In particular I would like to thank Patricia Munoz, Legal Advisor of PGEU, (Community pharmacists group), Roberto Frontini, President of the European Association of Hospital Pharmacists, Bart Rombaut, President of the European Association of Faculties of Pharmacy and Guilherme Monteiro Ferreira and Pedro Barroca Past-President and President respectively of EPSA (European Pharmacy Students Association). During the meeting, the EIPG installed new Bureau members Nuno Moreira (Portugal) as Vice-President Education and Careers and Gunther Pauwels (Belgium) as Vice-President European Affairs. Piero Iamartino (Italy) was re-elected as Vice-President, Technical and Professional Development. Regarding our strategic aims, it is the desire of the EIPG to continue to represent the interests of the individual Industrial Pharmacist and to ensure that we continue to produce pharmacists with the right skills to enter this exciting sector of pharmacy. Hence, the EIPG will actively champion the need for Universities to continue to teach Industrial Pharmacy as a core
discipline within the curriculum and to help those students who show an interest in a career within the Industry. I was very pleased to see members of EPSA attend the General Assembly and to actively take part in our discussions. For me, investing in the future means we need to look after our young talent and to nurture this talent, especially through difficult times. If any industrial pharmacist or student pharmacist needs advice about the Industry in their country, they need only to access our website and write to me, Mrs Jane Nicholson our Executive Director or any of our Bureau members. Finally, I would like to share the fact that in Paris in April this year, I was able to confer a Lifetime Achievement Award to Jean-Pierre Paccioni from France and who has been a member of the EIPG for over 15 years. Jean-Pierre has been a passionate and stalwart supporter of the European Industrial Pharmacist and of the EIPG and his support over the last 5 years and during these difficult times has been an enormous help to me as President. Sometimes readers forget that individuals such as Jean-Pierre and those within the General Assembly often give up a lot of their personal time and voluntarily contribute to make organisations such as the EIPG effective. Without these individuals, there would be no EIPG. I would like to wish you all a happy, warm and dry summer!
Gino Martini President
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SEVERE DRUG SHORTAGES – WHO’S TO BLAME? by Michael Anisfeld
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s you read this, there are severe drug shortages of oncogenic and other drugs in many countries. According to the United States Government Accountability Office1 there were shortages of 220 finished drug products in 2011. The FDA Coordinator of the Agency's Drug Shortage Program has said that 54% of the shortages were due to quality or manufacturing issues. In the USA, closure of Ben Venue Laboratories (BVL) Bedford, Ohio facility is likely to exacerbate a shortage of Johnson and Johnson’s Doxil that has persisted since the summer and has cut off treatment for many cancer patients. About 2,700 people are on a J&J waiting list to receive the drug, which is used to treat ovarian cancer, multiple myeloma and other cancers2.
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Michael Anisfeld is Senior Consultant, Globepharm, USA.
National Regulatory Agency (NRA) inspections performed at BVL’s Bedford facilities during 2011 resulted in the British and French authorities withdrawing Product Licenses (PL) from several companies that used BVL as their contract manufacturing source. BVL has been in business for over 70 years as a Contract Manufacturing Organisation (CMO) and specialised at its Bedford facility in the aseptic manufacture of many drugs, especially oncogenic drugs. BVL’s clients range from the largest multinationals to the smallest start-ups needing someone to make small batches of Phase II clinical trials supplies. BVL product was distributed and trialed/marketed by BVL clients around the world. A timeline of 2011 regulatory inspections at BVL shows that current company “troubles” began with a joint British (MHRA) and French (AFSSAPS) inspection in January/February 2011 which found many points of concern with basic GMP compliance and serious issues involved aseptic product manufacture (EU GMPs – Annex 13; a document equivalent to FDA’s
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Guidance on Aseptic Processing). They advised BVL of their concerns and through the FDA and MHRA Memorandum of Understanding their inspection findings were shared with FDA. This gave FDA qualms about the quality of product made at the Bedford facility and between May 2nd and 25th 2011 a team of between variously 6 and 14 inspectors inspected the facility, performing an in-depth GMP compliance investigation. This investigation resulted in a 33 page FD-483 listing of inspectional observations, containing 46 different areas of concern about BVL’s aseptic process operations issued to the company’s President and CEO 4. Areas of concern cited during this May 2011 inspection included (paraphrasing): • Failure to identify the root cause, or implement corrective actions, involving the presence of stainless steel particles, in BVL products. FDA notes eight different client complaints on this matter covering 17 batches of products; • Repeated failures to meet BVL’s
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own aseptic media fill (process simulation) criteria. One failure includes a BVL deviation report noting that “the media fill batch size is less than the batch size noted in the validation protocol”, but despite this notation the media fill was passed and deemed acceptable; BVL’s validation master plan specified the frequency of performing media fills, but this frequency was not adhered to; Clean room qualifications did not include assessment of air flow patterns under conditions of room usage; The sites of environmental monitoring used by BVL did not reflect BVL’s own procedures and failed to reflect actual operational conditions of clean room usage; Some sterility test failures were attributed to contamination by anaerobes, but the environmental monitoring program did not include testing for anaerobic contaminants; Over a 15-month period BVL had recovered at least 1,171 microbial contaminants, of which 1,047 organisms were Gram-positive. BVL failed to identify the root cause, or implement corrective actions to address the contaminations; No trending of microbial contaminations had been performed, nor had contaminants been identified to species and genus level; Despite the company having limits for non-viable contamination in clean rooms, these were exceeded 112 times during a 5-month period. Even though BVL required filling activities to halt if the automated system detected an OOS nonviable particle count, the remediation procedure employed did not include sanitising the filling lines; BVL did not keep records of pressure differentials of clean rooms and surrounding areas; Temperature and humidity of the sterile storage was not monitored, including during the
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SEVERE DRUG SHORTAGES – WHO’S TO BLAME?
occasions when rain water leaked from the roof through the HEPA plenum and into the sterile storage area; • Visual observation of clean room activities from the outside area was difficult in that door windows did not provide a full view of clean room operations; • The computer controlled stopper washer and depyrogenation tunnel is deficient in that there is no documentation of which individuals have access to which levels of password control. Additionally alarm reports for various out of limits tunnel operations are not reviewed or trended; • and on, and on … It seems that the authorities gave BVL time to clean up their act, literally, but in November 2011 a three week joint inspection by the FDA (4 inspectors including Mr Thomas Arista, FDA’s national expert on sterile product manufacture) and inspectors from AFSSAPS and MHRA returned to review remediation progress after the earlier inspections. The inspectors were in a quandary – BVL was the only manufacturer for many of the anti-cancer products; if they stopped the company manufacturing these products, patient therapy and safety was at risk. What to do – allow product onto the market with potentially lethal quality problems, or shut the facility and deprive patients of desperately needed anti-cancer therapy? The FD-483, issued to BVL’s new President and CEO following the November 2011 inspection runs to 11 pages and cites 10 areas of concern with each area having multiple sub-items of concern – many of them issues that had not been corrected from the 6-month previous May inspection. In mid-November the British and French withdrew the Product Licenses from several BVL manufactured products with a recommendation to the European Medicines Agency that this be a Euro-wide ban. Canada 5, Hong
continued
Kong and other countries have instituted similar action. In the USA, FDA convinced Ben Venue Laboratories to engage in a voluntary shut-down. The ripples of these regulatory product withdrawals have had worldwide reach. There seems to have been a chain of ineptitude in many spheres surrounding this entire issue at local, national and international levels, resulting in potential risk to patients. At the local level, where was BVL’s own QA group, and BoehringerIngelheim’s Corporate QA (BI was BVL’s parent company)? Didn’t their internal audits reveal these defects, and if they did why were the deficiencies found by FDA in 2011 allowed to remain unresolved. Surely these auditors had no constraints as to where in the factory they could audit – it appears that cleanroom operations could not be viewed without gowning and entering the work area which BVL consistently refused entry to client auditors and NRA inspectors 6. The 2011 quality concerns are not an epiphany regarding the BVL’s quality and GMP compliance concerns. BVL’s problems can be traced back over three decades since the 1980s with the MHRA (and its prior incarnations – DHSS and MCA) and the European Medicines (Evaluation) Agency having over a thirty year period pulled several Product Licenses (P/L) from companies where BVL was the CMO. Each time BVL, the world’s largest manufacturer of oncogenic injectable drug products, committed to make improvements and the need for these products resulted in a restoration of the P/L. In hindsight, remediation was always very slow and often incomplete, but patient needs trumped GMP compliance – such is the risk/benefit equation. How did BVL enter this quagmire? In BVL’s own words 7 they are “the oldest and most experienced manufacturer of lyophilised products in the United States”. If BVL has these problems, what is the
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Quality/GMP profile of other less experienced companies? Is it coincidental that when the GMP compliance problems came to light during these AFSSAPS, FDA and MHRA inspections, that the German parent company BoehringerIngelheim, who had owned BVL since 1997, announced that they would divest themselves of BVL to quote “concentrate on their core business” – which pray tell is what, if it is not pharmaceutical manufacture? Why did it take an overseas inspection by MHRA/AFSSAPS in the United States to shed light on these severe GMP deficiencies, before FDA went storming into the facility? Why had FDA’s much lauded risk management approach to GMP inspections not resulted in more frequent and tougher inspections? Seems that the regulators need to provide some answers. At the end of 2011 the EMA recalled all batches of Busilvex (Pierre Fabre Médicament), Ecalta (Pfizer Limited), Luminity (Lantheus MI UK Ltd), Velcade (Janssen-Cilag International NV) , Vidaza (Celgene Europe Ltd) and Vistide (Gilead Sciences International Ltd.) manufactured at Ben Venue 8. The EMA also asked healthcare professionals to take measures such as visually examining vials of Caelyx (Janssen-Cilag International), Ceplene (Epicept GmbH) and Torisel (Pfizer Limited) for the presence of metal particles – these last three products were not recalled. If the regulators have not been on the ball, what of the BVL/BI’s and BVL’s client companies’ Qualified Person (QP) in the supply of potentially life-threatening product to patients. Each of these seven European companies cited by EMA in their press release has a QP who has certified in a legal register that the products released to market conformed to GMP requirements 8 – when obviously the NRAs have disagreed and recalled product. How is it that the QPs (and their US cousins in QA groups who have an
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SEVERE DRUG SHORTAGES – WHO’S TO BLAME?
equally similar problem) allowed over many years multiple batches of nine products to be placed on the market that the British and French inspectors, and through them the EMA, deemed not to have been manufactured in accord with GMP? Will these QPs now receive censure from their certifying bodies (e.g., UK’s Royal Pharmaceutical Society) such as having their QP registration withdrawn for dereliction in performance of their duties? Such censure would immediately strengthen the QP’s position within the pharmaceutical industry and dramatically improve the QP’s oversight function. Obviously as well as the NRAs, companies’ QPs were deficient in their responsibility to safeguard and protect patients. Why is it that the GMP inspections by these authorities revealed a plethora of GMP failings while the routine audits/inspections by many company QPs (and for US companies, their QA groups) obviously did not find compelling reasons to cease sourcing their product from Ben Venue Laboratories? Several potential reasons might be at play: i BVL did not allow QPs in-depth access to data that the regulatory authorities were able to access. ii The QP’s inspection was not sufficiently rigorous to evaluate the true state of the contract manufacture’s GMP compliance profile. Compare how deep a GMP compliance assessment by one experienced contract giver auditor for two days, the typical time allotted to such audits, compares to what can be gleaned by 14 experienced government inspectors on-site for three weeks! iii Contract giver GMP compliance assessments are biased in favor of finding nothing critical and little of consequence during an audit – thus continuing the contract giver-contract receiver relationship. When registering a drug, the drug applicant states the name of the CMO, and all submitted stability and process validation data is based on the
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CMO’s involvement. If a QA/QP audit reveals significant GMP failures, then severing the contract giver/contract receiver relationship requires effectively being off the market for one – two years while an alternate CMO is found, stability and validation data generated and submitted to the authorities, and waiting for approval of the site change from the authorities. We are talking major money in making a decision to sever a relationship with a CMO. Many colleagues have told me of situations where they have been required by their company to significantly tone down their report. A QA/QP audit is inherently biased to continue the contract giver/receiver relationship such that contract giver’s sales and profits are not jeopardised; rarely do thoughts of patient safety enter the discussion, let alone appear in minutes of meetings to discuss whether to continue the CMO relationship. And if this is a problem with government NRAs who have legal clout to back up their inspections, and QA/QPs not faithfully fulfilling their duties when it comes to a CMO relationship for finished dosage forms where the NRA also performs independent inspections, how bad is it with Active Pharmaceutical Ingredient (API) where the European NRAs have essentially, with a few exceptions, abrogated their inspections responsibilities entirely in favor of trusting the QP’s audits of their API sources? Much better is the US system where, despite serious problems with FDA inspections that have been highlighted several times by Congress’ General Accountability Office, FDA performs its own inspections of API suppliers worldwide. A typical QP audit of an API source is one to two days by one auditor; a typical FDA inspection is two investigators for five days. 2011 has been an annus horribilis in GMP compliance for the US
pharmaceutical industry. What with the Johnson and Johnson Tylenol (acetaminophen/paracetamol) debacle and the almost complete removal of all Tylenol products from the US market; the US$ 650 million fine paid by GSK for GMP noncompliance issues; and now the BVL experience – we should all be very deeply concerned. Is all this a consequence of globalisation, or the worldwide economic malaise and the need to cut company quality oversight programs, or a move to ever leaner lower and middle management? Perhaps like the US meat processing industry where for at least 50 years a US Department of Agriculture (USDA) inspector is permanently based in each factory, we are headed for an age where an FDA inspector is permanently based in factories manufacturing critical pharmaceutical products? Much food for thought. References 1 2
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www.gao.gov/search?q=FDA http://online.wsj.com/article/ SB10001424052970203699404577048760 847025768.html?KEYWORDS=Ben+Venue +Laboratories http://ec.europa.eu/health/documents/ eudralex/vol-4/index_en.htm. The role and responsibilities of the QP is currently under review as discussed in an EMA Concept Paper issued in October 2011. The full, but partially redacted, FD-438 can be downloaded from FDA’s Electronic Reading Room at www.fda.gov/RegulatoryInformation/foi/El ectronicReadingRoom/default Health Canada (HPFBI) announced on August 17, 2011 an import ban on 17 products manufactured at BVL. Details are available at: www.hc-sc.gc.ca/dhpmps/medeff/advisoriesavis/prof/_2011/ben_ven_nth-aah-eng.php Personal communication from exFDA/MHRA inspectors www.benvenue.com/pages/history Article 51 of EU Directive 2001/83/EC and Article 55 of EU Directive 2001/82/ and EU Guide to Good Manufacturing Practice (July 2001)
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GI TRACT CHALLENGES – achieving in vitro in vivo correlations (IVIVCs) for controlled release dosage forms by Emma L McConnell, Hywel D Williams and Samuel R Pygall Introduction
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ontrolled release (CR) pharmaceutical dosage forms have several uses. They can (i) protect a drug, (ii) facilitate site-specific drug delivery, or (iii) prolong drug release in vivo. Whilst this approach offers significant advantages for the delivery of certain drugs (e.g. low solubility compounds, labile molecules or irritant substances) it extends dosage form exposure to the hostile environment of the gastrointestinal (GI) tract. Emma McConnell was formerly at MSD and Samuel Pygall is currently at MSD, Hoddesdon, Herts, UK; Hywell Williams is at Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
The challenge from physiological conditions throughout the gut can significantly modulate drug release and pharmacokinetics. This can be problematic in the fed state where food effects and gut motility may contribute to dose dumping or conversely, to reduced drug bioavailability. These are difficult to predict from simple in vitro tests and considerable efforts have been employed to detect problematic formulations by better designed dissolution testing methodologies which attempt to mimic specific aspects of the fed and fasted gastrointestinal tract. These bio-comparison studies require the concept of in vitro-in vivo correlations (IVIVCs). These describe the relationship between an in vitro drug release profile and the respective in vivo behaviour of the dosage form. Notably, the establishment of these relationships is often aided by an understanding of which in vivo factors may affect drug release. Difficulties arise when it is considered that in vitro the rate limiting step is dissolution into a media, whereas in vivo the rate limiting step may be drug absorption. IVIVC has several levels which can be achieved, ranging from level A to C, and these are
detailed in Table 1. Following achievement of a successful IVIVC, for which usually level A is desirable, the regulatory authorities may grant a ‘biowaiver’ following minor formulation changes, permitting the use of substitute in vitro dissolution assays for human pharmacokinetic studies. This is cost-effective for the industry, and has led to concerted efforts to generate appropriate testing methodologies to successfully mimic the GI environment. This includes: (i) the utilisation of various dissolution apparatus, (ii) the
development of biorelevant media and (iii) the development of an artificial gastrointestinal tract. Achieving IVIVC
Why is it often problematic to obtain IVIV correlations for CR dosage forms? The answer lies in the GI tract complexity and the exposure of CR dosage forms to the potentially adverse conditions of pH variability, ionic composition and variable gastric forces. In order to understand, or even predict the fate of these dosage forms, the gastrointestinal tract conditions should be considered. IVIVC and the stomach
Pre-exposure to acid in the stomach can affect integrity of dosage forms and drug molecules and can be assessed by pH change dissolution methods. Generally 0.1 N HCl is acknowledged as suitable media to assess gastric release, but simulated gastric fluid is comprised of HCl and sodium chloride, with or without the addition of pepsin. Often various buffer species are used to challenge dosage forms. The use of biorelevant media has been extensively researched and continuously updated by the Dressman group. These media contain various ions, bile salts, fatty acids, and the latest version uses a bovine milk based medium to represent a ‘snap shot’ of the fed stomach. This followed a series of studies which showed that high fat
Table 1. Levels of IVIVC Level
Requirement
A
This is a point-to-point correlation or one-to-one correlation, for example between fraction of drug absorbed and fraction of drug released in vitro. Level A correlations are considered the "holy grail" of IVIVC.
B
The mean residence time (in vivo) is compared to the mean in vitro dissolution time. This is done using statistical moments analysis, and although it uses all the in vitro and in vivo data, it is less useful than Level A, since it does not consider the shape of the in vivo profile.
C
This is a single point correlation, for example drug released in vitro at four hours with a pharmacokinetic parameter such as Cmax, AUC or Tmax .
Multiple Level C
This is when more than one single point correlation can be established
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continued
milk (3.5%) displayed similar physiochemical characteristics to that of a semi-digested, FDA test meal. Other work has shown that the nutritional drink Ensure Plus closely resembles the physicochemical composition of a homogeneised FDA meal; the upper intestinal aspirates of dogs and humans have been analysed following consumption of this drink to characterize accurately the surface tension, pH, osmolality and chemical make-up (Kalantzi et al 2006).
Although these food-mimicking media may represent certain aspects of a FDA test meal, their complexity also generates new obstacles to those who are required to perform in vitro dissolution testing in said media. These multicomponent media often require complex methodologies, but successful analyses have generated positive results; one example is Jantratid et al (2008b) who employed HPLC to quantify the release of a lipophilic drug from lipid formulated gelatin capsules into high fat milk diluted with an ionic rich buffer solution (FeSSGF) and demonstrated that this medium could generate an accurate level A IVIVC for this product. Although largely successful in ascertaining successful IVIVCs for poorly soluble drugs via solubiliserenhanced dissolution, the media do not fully represent the complex in vivo fed environment and are unlikely to precipitate in vitro formulation failure. In vitro tests often struggle to realise the extremity of the gastrointestinal
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environment, including pH or enzymatic challenge. Furthermore, it remains difficult to assess the susceptibility of formulations to internal physical pressures. IVIVC and the small intestine
Various efforts have been made over the years to define and utilize a representative medium of the small intestine, with concurrent mechanical stresses that accurately represent the in vivo situation. The most well-known is Simulated Intestinal Fluid (SIF) USP which currently has a pH of 6.8 designed to reflect the pH of the proximal small intestine. From this rather simplistic approach, concerted efforts have been made in the past decade to improve the dissolution media used to simulate the conditions of the small intestine resulting in the development of biorelevant media such as "Fasted State Simulated Intestinal Fluid (FaSSIF)" and "Fed State Simulated Intestinal Fluid (FeSSIF)". An important differentiation between these
examples of so-called "biorelevant" media and SIF is the incorporation of some important additional components of GI fluids, including bile salts and lecithin. The usefulness of these media for predicting in vivo dosage form performance has been demonstrated in a number of studies into pharmaceutical products. However, these systems are not infallible. For example, there is concern that the in vivo bile salt concentration is lower than that used in FeSSIF, leading to false positives with respect to drug dissolution performance. Conversely, FeSSIF contains no lipolysis products, which have been shown to act synergistically with bile salt conjugates, phospholipids and cholesterol to form mixed micelles, enhancing the solubility of poorly soluble or lipophilic drugs. Work remains on going to improve their performance and applicability to the in vivo situation. The mechanical stresses to which a dosage form is exposed within the small intestine are not easily replicated in vitro. To be close to in vivo conditions, in vitro methods should maintain all necessary conditions that can influence the behaviour of controlled release dosage forms. The simulation of the hydrodynamic effects in the GI tract is afforded by the rotational movements of the paddles or baskets using the USP II or USP I methods respectively or by the laminar flow rate of the dissolution medium using the USP IV method. However, the plethora of GI forces and stresses, particularly the peristaltic movements, cannot be simulated exactly. In addition, there is another force exerted on the tablets in vivo; the “peristaltic force� which results from the contraction and relaxation of GI muscles. The use of TNO-intestinal model systems goes some way towards addressing this issue. These models incorporate various aspects of motility, absorption and enzymatic and ionic challenge in a
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sequential and dynamic manner but they remain costly and timeconsuming methodologies. As the development of in vitro dissolution media and better mechanical stresses which mimic the small intestine in the fed and fasted state continues to progress, it should be appreciated that the small intestinal tract has by no means been fully characterised. As more data becomes available, its importance to achieving IVIVC should be assessed, and the complexity of the in vivo situation should not be underestimated. IVIVC and the large intestine
Satisfactory modelling of the large intestine can be technically difficult, and several key aspects are under debate. For example, should caecal or faecal material be employed, and should human or animal material be utilised?
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samples. Analysis can be difficult from such "dirty media". The presence of microflora is one of the defining features of the lower gut and this creates a fluctuating and dynamic environment raising yet another issue – should bacteria be incubated in simple buffer media, or should nutrients be provided? This may depend on the duration of the in vitro test, bearing in mind that transit through the colon can be many hours. Enzyme solutions are sometimes used as an alternative to faecal material, but their limitations in reflecting the true colonic environment should be acknowledged. Summary
In vitro in vivo correlations are an important and cost-effective objective for the pharmaceutical industry, particularly in these current economic times and scarcity of the once common pharmaceutical blockbuster. It is imperative that Changing bacterial populations fundamental research continues metabolic potential of bacteria into understanding Low viscosity the conditions of the gastrointestinal Long transit time environment and Changes in motility its influence on Changing pH drug liberation phenomena from controlled-release dosage forms. Whilst fully characterising and mimicking the complexity of the gastrointestinal tract may remain an Animal material allows elusive goal, uncovering and access to caecal and understanding the key parameters to colonic material, albeit in predict dosage form behaviour can small amounts if rats are be achieved. used. Access to human colonic contents is invasive, and only faecal Acknowledgements samples are relatively feasible for in We thank Drs Christian Seiler, David Storey, Steve Booth, Rob Ward, vitro studies. Should the material be diluted? The sample viscosity must Fabio Chiti and Henry Wu of MSD for constructive criticism of the be considered and dilutions are manuscript during its preparation. often required in order to take
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Further Reading http://www.ema.europa.eu/docs/en_GB/doc ument_library/Scientific_guideline/2009/09/ WC500003664.pdf http://www.fda.gov/downloads/Drugs/Guida nceComplianceRegulatoryInformation/Guida nces/UCM070239.pdf Basit AW, Short MD, McConnell EL. Microbiota-triggered colonic delivery: robustness of the polysaccharide approach in the fed state in man. J Drug Target 2009; 17: 64-71. Bieche I, Narjoz C, Asselah T, Vacher S, Marcellin P, Lidereau R, Beaune P, de Waziers I. Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues., Pharmacogenet. Genomics., 2007; 17, 731-742. Blanquet S, Zeijdner E, Beyssac E, Meunier JP, Denis S, Havenaar R et al. A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Pharm Res 2004; 21(4): 585-91. Cummings JH, Banwell JG, Segal I, Coleman N, Englyst HN, Macfarlane GT. The amount and composition of large bowel contents in man. Gastroenterology, 1990; 98, A408. Ibekwe VC, Khela MK, Evans D, Basit AW. A new concept in colonic drug targeting: a combined pH-responsive and bacteriallytriggered drug delivery technology. Alimentary Pharmacology & Therapeutics, 2007; 28: 911-916. Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update. Pharm Res 2008; 25 (7): 16631676. Kalantzi L, Persson E, Polentarutti B, Abrahamsson B, Goumas K, Dressman JB, Reppas C. Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents. Pharm Res 2006; 23: 1373-1381. Klein S, Butler J, Hempenstall JM, Reppas C, Dressman JB. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. Pharm Pharmacol 2004; 56; 605610. Klein S, Stippler E, Wunderlich M, Dressman J. Development of Dissolution Tests on the Basis of Gastrointestinal Physiology, In: J. Kramer, J.B. Dressman, (Eds), Pharmaceutical Dissolution Testing, London, Taylor and Francis 2005. McConnell EL, Fang L, Basit AW. Colonic treatments and targets: Issues and opportunities. J Drug Target. In press.
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STABILITY OF OMEPRAZOLE ORAL PREPARATIONS by MG Lee, AJ Charvill, S Young, HL Douglas and S Matumo
F
ollowing reports of lack of efficacy for generic omeprazole tablets when switching between brands, an investigation was conducted into the stability of omeprazole at acidic pHs and on the effectiveness of the gastro-resistant coat of different brands of omeprazole capsules at the pH range of the stomach. MG Lee, AJ Charvill and S Young are at the Medicine and Healthcare product Regulatory Agency (MHRA), 151 Buckingham Palace Road, London SW1W 9SZ, UK; HL Douglas and S Matumo are at the MHRA Laboratory, Laboratory of the Government Chemists (LGC), Teddington, TW11 0LY, UK. Email: ged5860@aol.com
The results indicate that, for the brand of omeprazole that was the subject of the defect report, the gastro-resistant coat could dissolve at pH 4.5 and this would potentially lead to the release and subsequent degradation of the omeprazole active ingredient in the stomach. Introduction
Omeprazole, a proton pump inhibitor used for the treatment of various gastric disorders associated with overproduction of acid and acid reflux in the stomach, degrades rapidly in acid solutions1,2. Therefore, oral solid dosage forms of omeprazole are coated with a gastro-resistant coat to prevent degradation in the acid environment of the stomach. In 2007, the Defective Medicines Reporting Centre of the Medicines and Healthcare products Regulatory Agency (MHRA) received an increasing number of reports of lack of efficacy of generic omeprazole capsules particularly when switching between brands. The number of reports suggested that there could be a quality problem with the product concerned. The pharmacopoeial dissolution test for gastro-resistant tablets and capsules requires testing at pH 1 for one hour, then at pH 6.8. The gastro-resistant coating should remain intact at pH 1 but release
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the active ingredient within 45 minutes at pH 6.8. However, testing at these two extremes may be inappropriate to confirm the stability of the product such as omeprazole during clinical use. This is because the pH of the stomach is variable. After meals or following treatment with antacids it can be as high as pH 5 or 63,4. Furthermore, during daily treatment with omeprazole, it will be above pH 4 for much of the time and may be as high as pH 5.5 5,6. Consequently, testing the resistance of the coating at pH 1 may not be sufficient to evaluate the stability of the coating throughout the potential pH range of the stomach. It is therefore possible that the reports of lack of efficacy may be due to dissolution of the gastro-resistant coat at these intermediate pH values, resulting in the release of the contents into the stomach and subsequent degradation of the omeprazole active ingredient due to the acidic conditions. This study was therefore undertaken to assess the effectiveness of the gastro-resistant coating of omeprazole tablets in the UK market at the pharmacopoeial limits of pH 1 and pH 6.8 and intermediate pHs. The study would identify any potential link between dissolution of the gastro-resistant coat at pH 4.5 and lack of efficacy.
Materials and methods Dissolution test method
Dissolution testing was performed in accordance with the British Pharmacopoeia 2007, Appendix XIIA using the apparatus described under test A, ie. a Distek, 7 stage, bathless dissolution apparatus. Analysis of omeprazole sample solutions
Omeprazole samples were analysed by HPLC in accordance with the method of the British Pharmacopoeia 2009. All analyses were performed in duplicate. Omeprazole standard
The omeprazole standard was obtained from AstraZeneca and revalidated using the assay for omeprazole in the monograph of the British Pharmacopoeia. Omeprazole preparations used
Three brands of omeprazole capsules and tablets were used for the study. One of these was the innovator brand and one was the generic brand that was the subject of the defect reports. Additional generic brands obtained as part of an earlier MHRA product quality surveillance study and a subsequent European market surveillance study of omeprazole products were analysed to confirm the validity of the revised method. Dissolution protocols
(i) Preliminary testing was performed for each of the three test brands of omeprazole capsules and tablets at pH 1, 3, 4, 5, 6, and 6.8, and in simulated gastric juice pH 4. (ii) From the preliminary test data, pH 4.5 was chosen as the intermediate pH for the dissolution studies. Three different protocols were evaluated. (a) A three-stage test at pH 1, then pH 4.5 and finally pH 6.8. (b) A two-stage test at pH 1 and pH 6.8, according to the pharmacopoeial method, plus an additional test at pH 4.5. (c) A two-stage test at pH 4.5 and pH 6.8. Hydrochloric acid (0.1M) was used
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as the pH 1 medium and phosphate buffer 0.05M at pH 4.5 and 6.8 for the buffered media. For the tests described under (a) and (c) above, pH was adjusted using 0.2M sodium dihydrogen orthophosphate and 10M sodium hydroxide. Samples for analysis were withdrawn from the dissolution media at 0, 15, 30, and 45 minutes. 2 x 5 ml samples were removed from the test media at each time interval and diluted to 25ml with pH 11 phosphate buffer to stabilise them. The diluted samples were analysed by HPLC. Results Table 1 gives the results of the
stability of omeprazole powder, 40mg, when subjected to different pHs over the range of the dissolution test. At pH 1 degradation is almost instantaneous and at pH 4.5 the sample is completely degraded within 45 minutes. When the release of omeprazole from the three tests brands at pH 3.0, pH 4.0, pH 5.0 and pH 6.0 was investigated, the results demonstrated that the product manufactured by company A exhibited clear differences from other products tested. The gastroresistant coating is showing signs of dissolution at the intermediate pH 4 and pH 5 7. Table 2 gives the results for omeprazole release from the three test brands using the two stage dissolution protocol at pH 4.5 and pH 6.8. Again there is evidence of release of omeprazole at pH 4.5 for brand A and, due to degradation at pH 4.5, only a small percentage of the dose is available after 45 minutes at pH 6.8. Figure 1, overleaf, shows the two dissolution profiles for company A and company C throughout the twostage test at pH 4.5 and pH 6.8. For company C the coating remains intact until the buffer change then releases 100% of its contents in the pH 6.8 buffer. In contrast, for the product from company A, the active ingredient is released immediately into the pH 4.5 medium due to
continued
Table 1. Stability of omeprazole at different pH. Percentage remaining at different time intervals. Each result is the mean of six determinations
pH 1 pH 1 stabilised to pH 11 pH 4.5 pH 4.5 stabilised to pH 11 pH 6.8 pH 6.8 stabilised to pH 11 pH 11
0
Time (mins) 15 30
45
4 8 0 54 39 75 96
4 3 0 15 34 80 101
3 1 0 0 23 70 98
4 2 0 4 29 84 101
Table 2. Dissolution data at pH 4.5 and pH 6.8 for three test brands of omeprazole tablets MA Holder
Strength (mg)
Company A Company A Company A Company A Company A Company B Company B Company B Company B Company C Company C Company C Company C
20 20 20 40 40 20 20 10 10 20 20 20 20
Dissolution % label claim mean of 6 doses dissolved pH 4.5 pH 4.5 pH 6.8 t = 0 minutes t = 45 minutes t = 45 minutes 0 6 18 0 5 11 0 5 9 0 13 11 0 1 9 0 3 94 0 1 99 0 2 101 0 2 95 1 3 100 0 0 94 1 1 100 0 0 102
dissolution of the gastro-resistant coating and is totally degraded by the time the pH 6.8 buffer is added. Discussion
The data from the pH stability studies clearly demonstrate the instability of omeprazole in acid solutions. Although the poor solubility of omeprazole in acid solutions confuses the data, they clearly show rapid degradation at pH 1 and 37°C and also significant degradation within 45 mins at pH 4.5 and 37°C. Dissolution of the gastro-resistant coating at pH 4.5 would be expected therefore to result in significant degradation of the active ingredient. The dissolution studies on the samples of the finished dosage
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forms showed clear differences between the suspect defective product and the other products tested. The gastro-resistant coating for the samples from company A disintegrated and allowed release of the omeprazole active ingredient in the pH 4.5 medium. The consequence of this is that the omeprazole degrades and so only a fraction of the dose is available after the pH 6.8 buffer stage. This is better demonstrated by the dissolution profiles for the products from company A and company C shown in Figure 1. For product C there is no release in the pH 4.5 buffer and immediate release at pH 6.8 with a plateau at approximately 100% after 20 minutes. For product A the omeprazole is released
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STABILITY OF OMEPRAZOLE ORAL PREPARATIONS
continued
Dissolution profile: Company A
% Release
100% 80% 60% 40% 20% 0% 0
20
40
60
80
100
120
80
100
120
Time (minutes) Dissolution profile: Company C
120%
% Release
100% 80% 60% 40% 20% 0% 0
20
40
60
Time (minutes) Figure 1: Dissolutions profiles for omeprazole capsules from Company A and Company C: 60 minutes at pH 4.5 then 45 minutes at pH 6.8.
immediately at pH 4.5 and the concentration of the active ingredient peaks after about 10 minutes, after which time the degradation rate exceeds the dissolution rate and the concentration falls. The net result is that there is no active ingredient remaining when the buffer is altered to pH 6.8. When product A was granted its licence, it would have been necessary to provide the Regulatory Authority with clinical and pharmacokinetic data to confirm its
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efficacy and its equivalence to other products on the market. However, healthy volunteer studies would not have identified the problem subsequently identified with the gastro-resistant coating since the resting gastric pH for such subjects would be pH 1. Furthermore the product would comply with the pharmacopoeial dissolution requirements for gastro-resistant preparations in force at that time. It is the somewhat unique combination of clinical effect and the instability of the active
ingredient in acid that gives rise to the problems identified during use. This study demonstrates also the value of post-marketing surveillance for quality problems. The introduction of monographs for gastro-resistant omeprazole capsules and tablets which include specific dissolution requirements now addresses these issue. Conclusion
The dissolution test data at the intermediate pH of pH 4.5 have clearly demonstrated that the gastro-
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resistant coating of the samples of omeprazole tablets that were subject of the defect report could potentially be defective. The standard pharmacopoeial dissolution method for gastro-resistant tablets does not detect it because the coating is stable at pH 1. It has, therefore, been necessary to introduce a specific test to detect this problem, which is particularly pertinent to omeprazole for two reasons. The clinical effect of daily dosing with omeprazole is a raised gastric pH which will be maintained above pH 4 and may be as high as 5.5. Secondly, omeprazole is rapidly degraded in acid media and at pH 4.5 the dose can be totally degraded if released in the stomach. The consequence for a product whose gastro-resistant coat dissolves at pH 4.5 is a potential lack of efficacy. The effect would be especially noticeable when switching from a brand which does not dissolve until pH 6.8 to one which may dissolve at pH 4.5, hence the problems experienced by patients receiving product A when switching between brands. In the BP 2009 the dissolution test for gastro-resistant omeprazole tablets and capsules was amended to include a test to confirm the stability of the gastro-resistant coat
continued
at pH 4.5 as the first stage of the dissolution test 8. Following the development and validation of the two stage dissolution test for omeprazole it was applied to samples of omeprazole products that had been obtained from the UK market as part of an earlier market surveillance study. The samples for this study were taken during 2006 and included samples from company A. The dissolution test was performed using the new method published in the BP 2009. Products from seven companies and of three different strengths, 10mg, 20mg and 40mg, were tested. Once again the product from company A failed the test. It had, however, complied with the existing dissolution requirements when tested during the 2006 study because the revised test was not applied. The retest was able to confirm that, other than Product A, all products on the UK market would comply with the new Regulatory requirements 7. As a consequence, the gastroresistant coat for this brand was reformulated and the defect problem resolved. The dissolution test in the British Pharmacopoeia monograph for omeprazole capsules and tablets has been amended to include a test at pH 4.5 and a market
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survey conducted to confirm that all brands of omeprazole tablets and capsules on the UK market complied with the test. References 1
2
3
4
5
6
7
8
Matthew M, Das Gupta V, Bailey RE. Stability of omeprazole solutions at various pH values as determined by High Performance Liquid Chromatography. Drug Develop Ind Pharm 1995; 21: 965–971. Quercia RA, Fan C, Liu X, Chow MS. Stability of omeprazole in an extemporaneously prepared oral liquid. Am J Health Sys Pharm 1997; 54: 1833–1836. Clark GWB, Jamieson JR, Hinder RA, et al. The relationship between gastric pH and emptying of solid, semi-solid and liquid meals. J.Gastrointest Mot 1993; 5: 273-279. McLaughlan G, Fullarton GM, Crean GP, and McColl KEL, Comparison of gastric body and antral pH: a 24 hour ambulatory study in healthy volunteers. Gut 1989; 30: 573-578. Keshavarz AA, Rahimi A. The effect of two different doses of omeprazole on gastric pH in ICU patients. IJMS 2004; 29: 40–42. Verdu EF, Armstrong D, Fraser R et al. Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut 1995; 36: 539–543. Lee MG, Charvill AJ, Young S et al. Stability of omeprazole oral preparations: effect of high gastric pH on the stability of the gastro-resistant coat. Eur J Parent Pharm Sci 2011; 16:73-77. The Department of Health. The British Pharmacopoeia 2009. The Stationery Office, Norwich, UK.
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EXCIPIENTS FOR THE FORMULATION OF MEDICINES FOR CHILDREN by Jennifer Walsh
T
he safety of excipients used in paediatric products is a key consideration for those formulating medicines for children. Jennifer Walsh PhD is Director at Jenny Walsh Consulting Limited, BioCity Nottingham, UK. Email: jennywalshconsulting@gmail.com Web: www.jennywalshconsulting.com
Introduction
In accordance with ICH principles, a scientific approach and quality risk management should be applied to the development of a pharmaceutical product and its manufacturing process1. The selection of type, quality attributes and amount of excipients is a key part of this process. The excipients used should be pharmaceutical grade and comply with the appropriate pharmacopoeial specification and/or regulatory requirements (as defined in the product Marketing Authorisation Application or Variation) and be manufactured, re-packaged and handled in accordance with GMP. It has been five years since the EU Paediatric Regulation2 came into force, in order to increase the availability of authorised medicines for children of all ages. The pharmaceutical development of paediatric medicines should follow the same principles as for products intended for adult use, although there are additional challenges, including the selection and use of excipients that are acceptable for this patient population, as discussed below. Excipient use in children Safety concerns
Excipients are generally considered to be "inert", although some have a recognised action or effect in certain circumstances, for example paediatric patients3. The CHMP Guideline on excipients in the
14
dossier for application for marketing authorisation of a medicinal product states 4 that "excipients to be used in formulations for the paediatric population should be selected with special care and possible sensitivities of the different age groups should be taken into consideration". It is proposed that the current CPMP Guideline on excipients in the label and package leaflet of medicinal products for human use be updated as a number of safety concerns regarding excipients have been identified that are not addressed, including the paediatric population 5. The paediatric population may be sub-divided into different groups, based on biological and developmental changes 6: • Preterm new born infants • Term newborn infants (neonates) (0-27 days) • Infants and toddlers (1 month –23 months) • Pre-school children (2-5 years) • School children (6-11 years) • Adolescents (12-16 or 18 years) During infancy and childhood, there is rapid growth and development with age-related changes in the various organs, body composition, protein binding, active transport mechanisms and metabolic pathways. Therefore, paediatric patients and in particular neonates and infants, may not be able to metabolise or eliminate an ingredient in the same manner as an
adult 6. Thus the toxicity of excipients may differ across the paediatric sub-sets and between adult and paediatric patients. There are few data available about the extent to which premature babies and neonates are exposed to excipients. Whittaker et al 7 calculated the quantity of excipients found in commonly used products that were administered to preterm babies. The amount of excipient each preterm baby received was determined on a per kg per week basis. Although any links between exposure and clinical outcome were not made, there was evidence that many of the infants in the study were exposed to excipient levels that were greater than the maximum accepted daily intake in adults. A second study focussed on neonatal exposure to benzyl alcohol and propylene glycol 8, where it was found that median cumulative doses of these excipients in patients who received medications via continuous infusion were approximately 21 and 180 times the acceptable daily intakes of benzyl alcohol and propylene glycol respectively. Examples of potential risks and clinical safety concerns associated with commonly used excipients have been described by Ernest et al 9 and Ursino et al 10. Although the latter review is not restricted to paediatric products, it identifies eleven excipients with a safety impact, many of which may be used in paediatric oral products. Indeed, excipient types that have been highlighted as having a potential to cause toxicological problems in paediatrics include preservatives (e.g. parabens, benzyl alcohol), sweeteners (e.g. sucrose, sorbitol, aspartame, saccharin), solvents (e.g. ethanol, propylene glycol) and colouring agents 6,11. Benzyl alcohol is no longer recommended for use in neonates. Reports of fatal toxic syndrome in premature infants have been reported as long ago as the early 1980's12 and exposure to benzyl alcohol has also been associated with the development of kernicterus and intraventricular haemorrhage in infants13. Sucrose may be used as a sweetener and also to give texture
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and improve mouth feel and palatability of oral liquids with the aim of facilitating patient adherence. There is a concern that chronic administration of products containing sucrose can increase the risk of dental caries and gingivitis in children14. Ethanol is found in many oral liquid products and is used as a solvent and/or preservative. Neonates and infants are not able to metabolise ethanol as efficiently as adults since they have immature alcohol dehydrogenase. Therefore, there is a high risk of toxicity associated with the use of this excipient in paediatric medicines which may lead to for example central nervous system (CNS) effects15. Propylene glycol, like ethanol, is a solvent widely used in formulations and adverse effects on the CNS have been reported in infants and children who have taken large doses7. Interestingly, unintended propylene glycol administration at a median dose of 34 mg/kg per 24 hours for a maximum of 48 hours has been found to be well tolerated in neonates, although the effects of longer term exposure are not known16. It has been recommended that the use of colouring agents in paediatric medicines should be avoided, especially azo dyes, since they have been associated with hypersensitivity and other adverse reactions 6,11. A study by McCann et al 17, the so-called "Southampton Study" found that artificial colours or sodium benzoate (or a mixture of both) in the diet of children aged 3 years and 8/9 years increased hyperactivity. However, an assessment of this study by the European Food Safety Authority (EFSA)18 concluded that the study provided limited evidence that the mixtures of colours and sodium benzoate tested had a small and statistically significant effect on activity and attention in the children evaluated, and that it was not possible to ascribe the observed effects to any of the individual compounds as mixtures were tested. In addition, it was concluded that
the clinical significance of the findings were unclear and that the findings of the study could not be used as a basis for altering the ADI of the colouring agents or sodium benzoate. There may be occasions where the use of colours may provide a benefit, for example to facilitate product identification and thus reduce the risk of mis-dosing, or for technical reasons such as the masking of an unpleasant drug colour. Colour has been found to affect the identification of a flavour by young children, for example, the association of red with strawberry flavour 19. Selection of excipients for paediatric formulations
The selection and use of excipients in paediatric formulations should be justified and take into consideration the functionality and safety profile of the excipient across the proposed paediatric patient population, duration of treatment and criticality of the condition to be treated 11. Type of dosage form will also clearly have an impact on excipient options. Liquid formulations are often administered to babies and children as dose adjustment according to body weight can be easily achieved by the administration of different volumes. Also, in the case of oral delivery, babies and young children may find liquids easier to swallow than solid dosage forms. It is of concern that many of the excipients above that have the potential to cause toxicological issues in paediatrics are often used in liquid products to for example, increase the solubility of the drug substance, provide preservation for multi-use products and increase palatability. It is therefore suggested that dosage form is carefully considered in addition to excipients to be used. A benefit/risk framework may be used to assess the comparative benefits and risks of different dosage form options, and also excipient options 20. Such an approach allows a rigorous, systematic and qualitative assessment of the merits and
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continued
disadvantages of each option and helps identify mitigating strategies to modify risk. It is acknowledged that there are limited safety data available on excipients in children. Indeed, ADI figures available tend to be based on adults. All potential sources of information should be assessed, for example literature, scientific guidelines, food legislation and EFSA11. The a priori use of an excipient in a paediatric product may also be of relevance although this evidence alone is not considered sufficient justification. It appears that many paediatric products that were authorised before the new EU Paediatric Regulation contain excipients that are now not recommended for children 21. Furthermore, there appear to be some differences in the acceptability of excipients across the globe, for example colouring agents and preservatives. The European Paediatric Formulation Initiative (EuPFI), which is a consortium of members from academia, hospital pharmacy and industry with a common interest in formulating medicines for children, has recognised the lack of information available on the safety of excipients in babies and children. The group are currently creating a database to provide a repository of information on excipients; Database of Safety Toxicity of Excipients for Paediatrics (STEP database) www.eupfi.org/gpage11.html. Summary
The selection of excipients to be used in paediatric products should follow the same principles as those applied to medicines intended for adults with the additional consideration of acceptable safety. Since there are biological and developmental changes throughout childhood, the toxicity of excipients may differ between adult and paediatric patients. An assessment of the safety of the proposed excipients in the intended paediatric population should be conducted and a benefit/risk approach used to justify their selection.
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References 1
2
3
4
5
6
7
8
9
ICH Topic Q 8 (R2) Pharmaceutical Development. Note for Guidance on Pharmaceutical Development and Annex EMEA/CHMP/167068/2004 Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use Volume 3B Guidelines Medicinal products for human use safety, environment information: Excipients in the label and package leaflet of medicinal products for human use, July 2003 CHMP Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product EMEA/CHMP/QWP/396951/2006 CPMP Concept paper on the need for revision of the guideline on excipients in the label and package leaflet of medicinal products for human use EMA/CHMP/SWP/888239/2011 CHMP Reflection paper: Formulations of choice for the paediatric population EMEA/CHMP/PEG/194810/2005 Whittaker A, Curries A, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F236-F240. Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med 2009;10(2):256-259.
Ernest TB, Elder D, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007;59:1043-1055. 10 Ursino MGm, Poluzzi E, Caramella C, De Ponti F. Excipients in medicinal products used in gastroenterology as a possible cause of side effects. Reg Toxicol Pharmacol 2011;60:93-105. 11 CHMP Draft Guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/180157/2011 12 Liston AJ. Toxic effects of benzyl alcohol. Can Med Assoc J 1983;128:8. 13 Jardine DS, Rogers K. Relationship of benzyl alcohol to kernicterus, intravascular hemorrhage, and mortality in preterm infants. Pediatrics 1989; 83(2):153-160. 14 Passos IA, Sampaio FC, Martinez CR, Soares de Morais Freitas CH. Sucrose concentration and pH in liquid oral pediatric medicines of long-term use for children. Rev Panam Salud Publica 2010; 27(2):132-137. 15 Zuccotti GV, Fabiano V. Safety issues with ethanol as an excipient in drugs intended for pediatric use. Expert Opin Drug Saf 2011; 10(4):499-502. 16 Allegaert K, Vanhaesebrouck S, Kulo A, Cosaert K, Verbesselt R, Debeer A, de Hoon J. Prospective assessment of short-term propylene glycol tolerance in neonates. Arch Dis Child 2010; 95(12):1054-1058.
24th - 26th September 2012
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McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, Kitchin E, Lok K, Porteous L, Prince E, Sonuga-Barke E, Warner JO, Stevenson J. Food additives and hyperactive behaviour in 3-year old and 8/9-year old children in the community: a randomised, double-blinded, placebocontrolled trial. The Lancet 2007; 370(9598):1560-1567. 18 Assessment of the results of the study by McCann et al (2007) on the effect of some colours and sodium benzoate on children's behaviour. The EFSA Journal 2008;660:1-54. 19 Oram N, Laing DG, Hutchinson I, Owen J, Rose G, Freeman M, Newell G. The influence of flavor and color on drink identification by children and adults. Dev Psychobiol 1995;28(4):239-246. 20 Sam T, Ernest T, Williams J, Walsh J. A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms – An application for paediatric dose form selection. Int J Pharm 2011 (submitted). 21 Strickley RG, Iwata Q, Wu S, Dahl TC. Pediatric drugs – a review of commercially available oral formulations. J Pharm Sci 2008; 97(5):1731-1774.
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SURVEY OF PHARMACEUTICAL EDUCATION IN EUROPE PHARMINE – Report on the integration of the industry component in pharmacy education and training by Jeffrey Atkinson, Jane Nicholson and Bart Rombaut Introduction
A
mongst PHARMINE work programmes (WP), WP7 is surveying pharmacists in different settings: community, hospital, clinical biology, industry and other sectors. The consortium also looks at how Pharmacy Education and Training (PET) in Higher Education Institutions (HEIs) is organised and adapted to the needs of practice. Jeffrey ATKINSON is Emeritus Professor, Lorraine University, Executive Director, Pharmacolor Consultants Nancy (PCN), Villers, (France). Jane NICHOLSON is Executive Director, European Industrial Pharmacists Group (EIPG), Paris (France). Bart ROMBAUT is President, European Association of Faculties of Pharmacy, Department of Pharmaceutical Biotechnology and Molecular Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussels (VUB), Brussels, (Belgium). Author for correspondence: J Atkinson at Jeffrey.atkinson@univ-lorraine.fr
The survey
The PHARMINE WP7 survey started in the spring of 2009. An electronic version was sent out to at least two HEIs per country (excepting countries with only one HEI, e.g. Estonia). HEIs then contacted their local pharmacy chamber (with the help of the Pharmaceutical Group of the EU, PGEU, their local European
Industrial Pharmacists Group, EIPG and their local European Association of Hospital Pharmacists, EAHP member). The questions in the first chapter of the WP7 survey on pharmacy practice were answered mainly by national member associations of the PGEU, EIPG and EAHP. The questions in the other chapters on
The PHARMINE consortium, consisting of pharmacy faculties and departments from countries of the European Higher Education Area (EHEA), members of the European Association of Faculties of Pharmacy (EAFP), together with professional organisations such as the European Industrial Pharmacists’ Group (EIPG), and national pharmacy chambers, surveyed industrial sector pharmacists. The consortium also looked at how European higher education institutions (HEIs) and courses are organised in relation to employment in industry. The PHARMINE survey thus produced country profiles with extensive information for each European country. EU directive 2005/36/EC does not allow for specialist pharmacy degrees such as a degree in industrial pharmacy.
european INDUSTRIAL PHARMACY June 2012
organisation of HEIs and courses, the effect of the Bologna declaration and the EU directive 2005/36/EC, and on quality assurance in HEIs were answered by members of the HEI. The design of the survey is balanced as we obtained data from at least one faculty per country. This paper describes the results obtained in 31 European countries (those obtained up to February 2012). Statview and nQuery programs were used. A comparison of nonparametric and parametric statistical analysis methods showed that the parametric tests are sufficiently robust in this context. A full report on the WP7 survey has been published. Results and discussion Status and numbers of pharmacists in industry
In very rare cases (e.g. France) the function of an industrial pharmacist (“pharmacien responsable”) is defined and recognised by government decree and is limited to those with a pharmacy degree . Qualified Person status in the European pharmaceutical industry is defined by EU directive 2001/83/EC . Whilst the directive does not restrict the status of the Qualified Person in the pharmaceutical industry to pharmacists, those with a degree in pharmacy will find it easier to fulfil the requirements than persons with another type of degree. In some countries (e.g. France) Qualified Persons must be pharmacists. In Germany, a Qualified Person must effectively be a pharmacist as there are no other courses that cover the
There is, however, a substantial element of research and industrial pharmacy in the fundamental pre-graduate pharmacy course with specialised, elective courses in industrial pharmacy subjects. Courses also have a large project work element (often scientific research) and a substantial element of pharmaceutical technology. Pharmacy HEIs are traditionally of either medical or scientific origin but this has no significant influence on courses given, viz PET in industrial pharmacy is not restricted to “scientific” pharmacy HEIs. Some pharmacy HEIs do have master degree courses in industrial pharmacy but these are open to graduates other than pharmacists and do not confer the right to registration for pharmacy practice.
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subjects required to be a Qualified Person. Industrial pharmacists are also identified by their membership of the industrial pharmacists’ branch of the national pharmaceutical chamber. This does not automatically imply that they have a status defined by EU or national government. The total number of pharmacists working in European industry is 37,308 (n=28 countries) out of a total number of industrial employees of 603,866 (n=23). Data are not available for all countries. The French confederation of pharmaceutical industries (LEEM) in their annual report (2011), show that >6,000 pharmacists out of a total workforce of 106,564, circa 6%, work in the French pharmaceutical and biotechnological industries. Fortyeight percent (51,151) of the industrial workforce are at managerial level (“cadre”) and pharmacists represent 12% of this workforce. The LEEM report shows that 53% of pharmacists work in production, 22% in R&D, 12% in regulatory affairs and 11% in marketing. As more than half work in production, this stresses the need for subjects such as pharmaceutical technology in pre-graduate PET for industrial pharmacy practice.
Impact of EU directive 2005/36/EC and the EHEA on PET
In Europe, degree courses qualifying for the sectoral profession of pharmacist are largely influenced by inter-state mobility of practising pharmacists. This is linked to the need for harmonisation in European pharmacy practice. With this in mind, European PET is organised in accordance with the EU directive 2005/36/EC. This specifies that (1) studies are of 5 years duration, (2) there is a sixmonth traineeship, and (3) the course includes defined basic elements. However, whilst the directive recognises various forms of medical specialisation (e.g. cardiology), it does not recognise specialisation in pharmacy (e.g. in industrial or hospital pharmacy or clinical biology). The above three items of directive 2005/36/EC govern PET in member states and in candidate countries (Iceland, Macedonia, Montenegro and Turkey) and several partner countries. Important efforts are being made in partner countries, helped by the EU TEMPUS (Trans-European Mobility Programme for University Studies) programme, to bring PET in such countries in line with the EU directives.
Pre-graduate PET for industrial pharmacy practice
The PET model
In all countries surveyed there is no separate diploma for industrial pharmacy – only a unique diploma for pharmacy, albeit in some cases there is the possibility of pregraduate elective courses in industrial pharmacy within the MPharm course. Where a full pregraduate master course for industrial pharmacy does exist (Italy, Belgium), it does not deliver the automatic right to exert the sectoral profession of pharmacist, although, in Italy, the integrated course in Pharmaceutical Chemistry and Technology can lead to the right to register as a pharmacist if the student follows the community/hospital pharmacy traineeship.
EU directive 2005/36/EC underlies the PET model with courses emphasising background and generic skills in the first years and introducing pharmacy-specific subjects like pharmaceutical technology later. Almost all faculties introduce some element of traineeship/student placement early (in the 1st, 2nd or 3rd years) but the main traineeship period is in the final years. Such seamless, five-or six-year integrated courses run in almost all countries (27/31 countries = 87%) surveyed. In four countries (Austria, Germany, Ireland and the UK) there is an integrated 4-year course at the HEI, followed by a 6- or 12-month traineeship.
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continued
The Bologna declaration
Another element affects HEI courses in general: the Bologna declaration. In order to facilitate movement of students amongst European countries, the Bologna declaration within the EHEA aims to harmonise the organisation of courses at HEIs. One element of this is the standardisation of the structure of the degree course into bachelor (first 3 years) and master (4th and 5th years) degrees. This PET model applies to all HEI courses not only pharmacy. It centres on not only freedom of movement from one country to another, but also on freedom of movement between courses with different exit and entrance possibilities at the bachelor-master junction. The WP7 survey showed that this Bologna model is not applied in European PET, although “academic” bachelor degrees are awarded in some countries such as Belgium. Furthermore, the Bologna declaration aims at improving ERASMUS exchange of students but the latter is difficult in PET at least in the early years. This is due to the fact that in addition to the difficulties faced by all students (finances, lodging, etc.) the pharmacy student faces an additional difficulty in that the subjects to be studied are specified in EU directive 2005/36/EC and there may be no temporal coincidence between subjects given in different faculties. For instance, for a 3rd year student whose home HEI teaches a given subject “Y” in the 3rd year whilst his/her host HEI teaches that subject in the 4th year, either the student does not receive instruction in subject “Y”, or his/her home HEI insists that the 3rd year is repeated in the home HEI. Such difficulties are less restrictive in the 4th and 5th years that are often devoted to electives in subject areas such as industrial pharmacy and project work (not under the aegis of the EU directives). This opens up opportunities for interaction
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PET and the industrial pharmacist workforce
No one is fully competent immediately after graduation although all pharmacists (and not just those going into industry) should have reached the "knows how/shows how" level of the industrial competencies by the time they graduate from university. Furthermore, some industrial pharmacists obtain their industrial competences at the post-graduate level by following courses such as the VUB advanced master course or the PIAT courses (see below). An EIPG survey of its members showed that most industrial pharmacists do not go on to study for advanced masters; many of them go on to take diplomas or participate in courses on law, marketing, management, etc. Furthermore, for some industrial pharmacy jobs, such as those in regulatory affairs or medical information, there is a
preference for a pharmacist with prior work experience in hospital or community pharmacy. Research/thesis project
All faculties propose project work to students. This is essentially some form of research project. Students spend an average of 677±154 hours over the 5 years of the course on such projects; this represents 13% of total course hours (n=31). In Norway, half of the time during the last 1.5 years is spent on project work and the other half on electives that support the project work. "Medical" or "chemical" orientation of PET
Over half the departments surveyed (16/31, 52%) are part of a faculty of medicine (or of a faculty of medicine and pharmacy). Twentytwo percent (7/31) are part of a science faculty, and 26% (8/31) are independent faculties. In accordance with EU directives 2001/83/EC and 2005/36/EC, over 70±7% of the fundamental pharmacy course is dedicated to three core subject areas: chemical sciences, medical sciences and pharmaceutical technology. There is an inverse relationship between the hours spent on chemical subjects
and those on medical subjects Figure 1). Thus degrees in some (F faculties are more “chemically” oriented and in others more “medically” or “clinically” oriented. In western European faculties, the two are even further developed into “product” and “patient” orientations. Contrary to hearsay, this situation does not depend upon the origin or adhesion of the HEI. Globally 1,189±127 and 1,116±118 hours over 5 years (n=31) are spent on medically and chemically oriented subjects, respectively. These figures are 1,277±156 and 1,110±145 hours (n=16) in departments that are part of medical faculties, 1,356±359 and 1,164±296 hours (n=8) for independent faculties, and 796±102 and 1,073±264 hours (n=7) hours in departments that are part of a science faculty. Thus departments with a medical attachment have 1.6 more hours (P < 0.04, t-test) dedicated to medical subjects than those of faculties with a scientific attachment – their courses tend to be more “medical” than “chemical”. Pharmaceutical technology
An average of 628±57 hours (n=31, 11.6±1.1 % of total degree duration) is spent on pharmaceutical
medical sciences %
between HEIs in developing PET for industrial pharmacy. Thus, for example, small(er) HEIs that find it financially too onerous to organise a complete course in industrial pharmacy, could come together with other HEIs, possibly in other countries in the same region, to produce a full course. The average faculty has 75±9 staff and 118±14 registered pharmacy graduates per year (n=31 faculties in 31 countries). Thus the student to staff ratio is low: 8 to 1. A proviso should be added here. In countries (UK and others) in which student w /year) are fixed to fees (circa 12kw cover the global expenses of the education of a student, it is judged that a much higher student to staff (full-time equivalents) ratio of 17-20 is economically viable. Albeit, in other countries, tuition fees are very low (e.g. France) or zero (e.g. Finland), so a different economic model applies. Furthermore, the PHARMINE WP7 survey did not check whether or not a given HEI used part-time, less qualified persons (e.g. final year doctoral students) for some specific forms of teaching such as practicals.
continued
chemical sciences % Figure 1: Inverse relationship between hours (% of total course duration) spent on chemical or medical sciences (n=27/31 countries).
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technology. The percentage in medically oriented faculties is 11.5±1.2, in independent faculties 14.7±3.5, and in scientifically oriented faculties 8.9±1.5%. There are no statistically significant differences between these percentages. It should be noted that a quarter of course time is spent on either project work or pharmaceutical technology. Industrial pharmacy aspects of pre-graduate PET
Ten faculties out of 31 have specialised, elective pre-graduate courses in industrial pharmacy (32%, n=31). These are generally in the 4th and 5th years and in some cases they are in the form of so-called “master” courses. In all cases, electives in industrial pharmacy (or in any other subject) allow registration as a pharmacist. In the pharmacy degree structure of the faculty of pharmacy of Lorraine University, Nancy, France, both “clinical” and “industrial” options are available in addition to community pharmacy and clinical biology. The industrial pharmacy option offers industrial traineeship and specialised M2 courses in various aspects of industrial Table 1). pharmacy (T In the VUB course in the Flemish part of Belgium the bachelor in pharmacy degree is an academic qualification obtained after 3 years
that leads to a master in pharmacy (pharmaceutical care) but does not represent a qualification for the job market. The master in drug design course is also open to graduates that do or do not have a pharmacy bachelor qualification. It prepares students for work in industry but does not confer the right to work as a registered practising pharmacist. Post-graduate courses in industrial pharmacy
Eleven faculties out of 31 propose post-graduate industrial pharmacy degrees (35%, n=31); acceptation onto such courses is not limited to possession of a degree in pharmacy. Typing the key words “industry” and “pharmacy” into the on-course® site of EMTRAIN – the European Medicines Research Training Network of the Innovative Medicines Initiative – reveals 629 such courses throughout Europe. Here two examples will be given. VUB in the Flemish part of Belgium offers a 6th year “advanced master” degree in industrial pharmacy. The PIAT (Pharmaceutical Industrial Advanced Training) programme of the School of Pharmacy and Pharmaceutical Sciences of the University of Manchester, UK also offers postgraduate course in industrial pharmacy. Quoting from their website: “Developed in partnership with the pharmaceutical industry, the PIAT programme is a postgraduate-
continued
level training programme designed for scientists and managers working in the pharmaceutical industry in the fields of Product Development, Manufacturing and Quality Assurance.” Courses are organised on a part- or full-time basis and are distance learning or in-house. Conclusions
EU directive 2005/36/EC does not allow for specialist pharmacy degrees such as a degree in industrial pharmacy. There is, however, a substantial element of research and industrial pharmacy in the fundamental pre-graduate pharmacy course with specialised, elective courses in industrial pharmacy subjects. Courses also have a large project work element (often scientific research) and a substantial element of pharmaceutical technology. Pharmacy HEIs are traditionally of either medical or scientific origin but this has no significant influence on courses given, viz PET in industrial pharmacy is not restricted to “scientific” pharmacy HEIs. Some pharmacy HEIs do have master degree courses in industrial pharmacy but these are open to graduates other than pharmacists and do not confer the right to registration for pharmacy practice.
Table 1: The industrial pharmacy degree structure of the faculty of pharmacy of Lorraine University, Nancy, France. Year
Courses
1
Basic health sciences study programme (together with students in medicine and dentistry)
2-4
Common (together with students in community, hospital pharmacy and biomedical analysis) pharmacy study programme with community pharmacy traineeship. Elective courses in industrial pharmacy subjects
5
6 months: hospital pharmacy traineeship 6 months: industrial pharmacy programme and traineeship in industry Possibility of double degree course with pharmacy plus, for instance, degree in chemical engineering
6
Master 2nd year M2 (elective): medical engineering, pre-clinical drug evaluation, etc.
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book review Quality in the manufacture of medicines and other healthcare products by John Sharp Reviewer: Dave Sharma For more than 40 years, John Sharp has played a key role in the development of European legislation for Good Manufacturing Practices. What we have in this second edition (suitably coloured Orange) is Sharp’s magnum opus. He conveys everything you need to know about the quality of manufactured medicines in a comprehensive yet compelling manner. It is a must read for anyone working in the field of Quality. Whilst at first glance, it may appear as an extended version of the Orange Guide, it is actually so much more. In fact, there are eight detailed sections with expanded parts on sterile products, validation and risk management. It is impossible not to admire the depth and breadth of knowledge the author reveals in this volume. The anecdotes from his experiences nicely balance the learned with the conversational. The result is a book that builds on and reorganises the previous edition and also incorporates new material. The emphasis on people as the most important aspect of assurance of quality served a reminder to the reviewer: ‘Nothing, not even the finest premises, equipment, materials or procedures can compensate for the quality hazard represented by low standard, ill-trained or badly motivated staff’. The wider implications of GMP/Quality are too often missed by organisations. Often, key individuals within Quality Departments seem to be driven by fear rather than by the assurance of quality. The chapter on ‘quality gurus’ is succinct and again underlines the human element to any quality system: ‘In a nut-shell, for medicinal products to be fit for their purpose, it is essential that the people involved in making them should themselves be fit for that purpose’. He delivers the section on Production planning in his ‘matter-offact’ style. Poor planning ultimately leads to ‘chaos inducing panic production’ which can have a serious impact on quality. My only real criticism is that there is no mention of the recent legislative changes in the Clinical arena. The Clinical Trial Directive (2001/20/EEC) came into effect on the 1st May 2004. Since that time, GMP is necessary for investigational products. There is now a
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new role of a Qualified Person for Investigational Medicinal Products [QP(IMP)]. Individuals went through a ‘grandfather’ transitional arrangement until 2006. Annex 13 – the Manufacture of Investigational Medicinal Products was updated in 2009. The responsibilities for a QP(IMP) are different to a Permanent Provision QP but this seems to have been overlooked in the second edition. There is, however, the update on GMP for Active Pharmaceutical Ingredients (APIs). What was Annex 18 has now become Part II: Basic Requirements for Active Substances Used as Starting Materials. The update is brief yet the adoption of this piece of legislation is proving to be a challenge for the industry. The onus is rightly placed on the pharmaceutical/medicines manufacturers to ensure that all principles of GMP are applied to active substances. For those of us who work in the field of Quality, it is very easy to lose sight of the real objective, that is, “the safety, well-being and protection of the patient”. In all the madness around us, this book will serve as a timely reminder of what we are supposed to be doing. Dave Sharma is a QP and also the Associate Director at Genzyme Europe. Email: dave.p.sharma@gmail.com Published by PHSS 2011 (2nd Edition) ISBN: 9781905271214 Paperback. 436 pages. Price £49.50
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regulatory review Introduction In the current review period there has been a number of changes in the regulation of medicines and regulatory guidance in the EU, International markets and the USA
United States of America Draft guidance – Use of certain Phthalates as excipients in CDER regulated products
Exposure to dibutyl phthalate (DBP) and di( 2-ethylhexyl) phthalate (DEHP) from pharmaceuticals presents a potential risk of developmental and reproductive toxicity. All drug products may carry inherent risks, but DBP and DEHP are used as excipients, and safer alternatives are available. The Agency recommends avoiding the use of DBP and DEHP as excipients in CDER regulated products and generally does not consider DBP or DEHP safe or suitable as an inactive ingredient in OTC monograph products. 21 CFR revision of certain labeling controls
FDA is amending the packaging and labeling control provisions for limiting the application of special control procedures in the use of cut labeling to immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons. FDA is also permitting the use of any automated technique, including differentiation by labeling size and shape, that physically prevents incorrect cut labeling from being processed. The intention is to protect consumers from labeling errors more likely to cause adverse health consequences, while eliminating the regulatory burden of applying the rule to labeling unlikely to reach or adversely affect consumers. Manufacturers may now use a broader range of error prevention and control techniques than permitted by current CGMPs.
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Europe Draft guideline on Process Validation
CHMP has released this updated guideline for consultation. The guideline is brought into line with ICH Q8, Q9 and Q10. Continuous process verification (CPV) has been introduced as an alternative approach to process validation. A lifecycle approach should be applied linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production Guideline on Real Time Release Testing (RTRT)
This guideline (formerly Parametric Release) has now been released and comes into effect 31 October 2012. It outlines the requirements for applications that propose RTRT for active substances, intermediates and finished products. It also outlines the different requirements that have to be fulfilled in the application and the need for interaction between quality assessors and GMP inspectors in the approval process. RTRT may result in the elimination of all, or certain, specific tests in the specifications of the finished API or finished medicinal product. EDQM progresses with e-TACT
by Malcolm Holmes progress to implementation within the regions This new guidance is for Active Pharmaceutical Ingredients (both chemical and biotechnological/ biological entities). Harmonising the scientific and technical principles relating to the description and justification of the development and manufacturing process in the Common Technical Dossier (CTD) China Chinese GMP (2010 revision) – English language version
SFDA has now published an English language version of the latest GMP. which in general follows EU GMP Guideline Part I, but includes some topics which the EU GMP deals with in annexes. Modern GMP concepts such as Quality Risk Management, management responsibility and CAPA are included. Chapter 3 includes considerable reference to the Qualified Person in terms of Qualification/Role & responsibility. Chapter 4 requires that the exposed processing areas for oral liquid and solid preparations, as well as the exposed processing areas for handling immediate packaging materials should be designed as Grade D PIC/S Aide Memoire Quality Risk Management
The Council of Europe and EDQM have specific obligations towards patients. EDQM considers the approach so far taken by industry as insufficient, as it does not include the possibility for patients to verify the authenticity of any pack of medicines they receive.
The purpose of this document is to assist GMP inspectors in the assessment of QRM implementation in industry during regulatory inspections.
International
For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies and to current and past editions of “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact info@euromed.com.
International Conference on Harmonisation Development and Manufacture of Drug Substances ICH Q11
ICHQ11 reached Step 4 of the ICH process in May and will now
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news from the EIPG General Assembly At the beginning of May, delegates from 14 countries met in Lisbon to attend the 2012 General Assembly. Following extensive consultation over the past year, the new Statutes of EIPG were adopted. Membership has been widened to include the European Economic Area and European countries having a mutual recognition agreement with the European Union on compliance control of regulated medicines. The Industrial Section of the Norges Farmaceutiske Forening (NFF) was elected as our first member under the new criteria. Wenche Gordon, industrial pharmacist from NFF, presented information on her Norwegian Association and on the pharmaceutical industry in Norway. Her slides and the reports from other members on their National Association’s activities during the past year can be found on our website (www.eipg.eu) under ”Member States”. Claude Farrugia, Vice-President Communications, and Joe Ridge, Editor of the Journal discussed the traffic on the website and the increasing number of hits on technical articles in the Journal.
Bart Rombaut, President of the European Association of Faculties of Pharmacy presented the ongoing work with PHARMINE 2 and the proposed development of a quality assurance system and the plans to establish a multi-site European distance learning modules to provide advanced training for industrial pharmacists. The meeting divided into two working groups. One discussed the Annex 16 concept paper on the Qualified Person and the submission of EIPG position papers on draft guidelines and concept papers from the European Medicines Agency and the Commission. The second group discussed the implications of the Free Movement Directive and the opinions of the European Associations of community, hospital and academic pharmacists were presented by our guests. The Executive Director of Apipharma, Heiter Costa, reported on the pharmaceutical industry in Portugal and his Trade Association’s objectives to support a sustainable National Health Service.
Friday Symposium On the Friday before the General Assembly, 120 industrial pharmacists and students of pharmacy attended
a Symposium at the University on ”the Challenges Facing the Pharmaceutical Industry” chaired by Nuno Moreira, President of the Industrial Section of the Portuguese pharmacists Association. Carlos Barbosa (President of the Ordem dos Farmaceuticos) introduced the Symposium and provided a pharmacists overview of the health care system, the ”Portuguese Reality”. In his description of the ever changing face of the pharmaceutical industry, Gino Martini, EIPG President provided a view of the future industry and its workforce. The recently introduced French pharmaceutical record with its fully integrated pharmacy software and automatic batch recall services were described by Jean-Pierre Paccioni, EIPG Treasurer. The Implications of Implementing the Directive on Falsified Medicines (anticounterfeiting measures) proposed by the European Commission were reviewed by Claude Farrugia, EIPG Vice-President Communications. The slide presentations for the Friday Symposium can be found on our website (www.eipg.eu) Jane Nicholson, Executive Director EIPG
EPSA Annual Reception “Active and healthy ageing – understanding the implications of growing old” In March, the European Pharmaceutical Students’ Association (EPSA) held its Annual Reception at the European Parliament, in Brussels and Philippe Bollen (VAPI/UPIP) attended on behalf of EIPG. During this event, the EPSA executive gave an overview of activities and achievements from the previous year (2011). The reception allows exposure to external bodies
such as professional organizations, European institutions, other student organisations and companies, and is typically followed by a round table/panel discussion on a well selected hot topic. EPSA collaborates with Members of the European Parliament (MEP) on providing the best content for participants and a number of MEPs were present at the Symposium.
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With a total of around 150 attendees, the Annual Reception has a broad interest and allows great networking opportunities. During the panel discussion, all the representatives emphasised that it is time to work on active and healthy ageing as the population of ageing people is growing, their specific problems arise day after day and very little has been done for them.
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events JULY
AUGUST
4 July 2012 – Dublin, Ireland Bio-contamination control & monitoring seminar www.phss.co.uk
9 August 2012 – York, UK Basics and practice of steam sterilisation www.nsf-dba.com
5 July 2012 – Stevenage, UK Fundamental method development www.jpag.org 5-6 July 2012 – London, UK Understanding ‘small molecule’ generic medicines www.pharmaqmtraining.eu/brochu res/generics.html 9-10 July 2012 – London, UK Social media in the pharmaceutical industry www.social-media-pharma.com 9-11 July 2012 – Manchester, UK Practical implementation of quality by design www.nsf-dba.com 11-12 July 2012 – London, UK Enabling research by improving access to samples www.bio-banking-event.com 17-18 July 2012 – Milan, Italy Good documentation practices www.nsf-dba.com 19-20 July 2012 – Berlin, Germany Filing variations www.ptiglobal.co.uk/filingVariations 24-25 July 2012 – Brussels, Belgium Adverse event reporting & pharmacovigilance www.pti-global.co.uk/adr
SEPTEMBER 9-10 September 2012 – Birmingham, UK RPS Annual Conference 2012 www.rpharm.com 9-13 September 2012 – Torun, Poland International Symposium on Chromatography www.chromsoc.com 11-12 September 2012 – London, UK World Biosimilars Congress 2012 www.terrapinnmedia.com 11-13 September 2012 – Manchester, UK Practical application of quality risk management www.nsf-dba.com 13 September 2012 – Nottingham, UK JPAG Symposium at the APS UK PharmSci Conference 2012. What is the future of dissolution testing? www.jpag.org 13-14 September 2012 – London, UK Adverse event reporting & pharmacovigilance www.pti-global.co.uk/adr
19-20 September 2012 – London, UK Biosimilars and biobetters www.biosimilars-biobetters.co.uk 24-26 September 2012 – Dusseldorf, Germany 11th Annual Biological Production forum 2012 www.girp.eu
OCTOBER 1-2 October 2012 – Dublin, Ireland Medical device regulation in Europe: Now and the future www.topra.com 3-8 October – Amsterdam, Netherlands FIP Centennial 2012 www.fip.org/amsterdam2012 22-23 October 2012 – London, UK COPD: Novel therapeutics & management strategies www.copd-conference.co.uk 22-24 October 2012 – London, UK 3rd Annual clinical relevant drug transporters www.drugtransporters.com 24-25 October 2012 – London, UK Point of care diagnostics: economic reimbursement & technology implementation www.pointofcarediagnostics.com 24-25 October 2012 – Berlin, Germany 10th Annual Bioproduction www.bio-production.com
www.fip.org/amsterdam2012
3-8 OCT 2012 AMSTERDAM, THE NETHERLANDS FIP’S WORLD CONGRESS OF PHARMACY AND PHARMACEUTICAL SCIENCES banner_H_EN_print_35x125.indd 1
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