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PHARMACY FEATURES 4
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EIPG GUIDANCE ON CPD FOR REGULATORY AFFAIRS
The European Industrial Pharmacy Group (EIPG) has prepared a Continuing Professional Development (CPD) Guidance for regulatory affairs professionals. by EIPG Regulatory Affairs members from France, Germany and UK PHARMACY EDUCATION IN HUNGARY Pharmacy education in Hungary has a long history and a great tradition. Professor Marton gives details of the curriculum, especially postgraduate education, whether for specialisation or for a doctoral degree. by Sylvia Marton SURFACE ANALYSIS EXPOSES COUNTERFEIT MEDICINES A technique from analytical chemistry could be useful in detecting counterfeit tablets. by Justine Bentley CHONDROCELECT: THE FIRST ADVANCED THERAPY MEDICINAL PRODUCT IN EUROPE A tissue engineered product for repairing damaged cartilage is the first to be approved by EMEA under the new ATMP regulation. by Tom Sam IN SITU GEL-FORMING SYSTEMS FOR SUSTAINED OCULAR DRUG DELIVERY Topical application of an ophthalmic product provides poor bioavailability. This can be overcome using a solution that shifts to a gel-form under certain physiological conditions. by Mahesh N Mali and Ashok A Hajare
REGULARS
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EDITORIAL COMMENT REGULATORY REVIEW NEWS FROM THE EIPG PHARMACEUTICAL FORUM JOB VACANCIES DATES FOR YOUR DIARY
ISSUE 5 • FEBRUARY 2010
www.industrialpharmacy.eu www.eipg.eu
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Associate Editors
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Belgium: Philippe Van der Hofstadt Bulgaria: Valentina Belcheva
Issue 5 February 2010
Czech Republic: Miloslava Rabiskova
ISSN 1759-202X
Denmark: Michiel Ringkjøbing Elema
EDITOR Joe Ridge, MRPharmS PRODUCTION Sue Feather
Finland: Tuula Lehtela France: Jean-Pierre Paccioni
SUBSCRIPTIONS Jill Monk
Germany: Armin Hoffmann
EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes John Jolley Sylvia Marton Pär Tellner
Great Britain: Jane Nicholson Greece: Kiriasis Savvas Hungary: Sylvia Marton
European Industrial Pharmacy is published three times a year by: Euromed Communications Ltd Passfield Business Centre, Lynchborough Road, Passfield, Liphook, Hampshire GU30 7SB
Ireland: Anna O’Mahony Italy: Piero Iamartino Latvia: Inta Saprovska Malta: Claude Farrugia Netherlands: Ineke Kleefsman, Michiel Storimans Portugal: bastonaria@ordemfarmaceuticos.pt
Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223 Email: info@euromed.uk.com www.industrialpharmacy.eu Annual subscription rate £58
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Spain: Mercé Pujol
discussion group:
www.pharmweb.net/gmp.html
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Views expressed in European Industrial Pharmacy are those of the contributors and not necessarily endorsed by the Publisher, Editor, Editorial Board, or by our corporate sponsors who accept no liability for the consequences of any inaccurate or misleading information
Switzerland: Renato Kaiser
©2010 Euromed Communications Ltd
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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Cover picture: Optical image showing crosssection of tablet whose manufacturing process was being deduced (see p14).
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E D I TO R I A L C O M M E N T Dear Colleagues Welcome to the year’s first edition of the European Industrial Pharmacy journal. Clearly, events of recent days have perhaps taken the shine off the new year already with announcements of restructuring occurring throughout the industry. In addition, the ever increasing focus on emerging markets seems to be the mantra of all CEOs regardless of company and size. In fact, as I write this I am sitting in Beijing awaiting a meeting with some vendors and I just have to say that scale is everything. You can drive for 3 hours in Beijing and you would still be inside the Beijing district line! However, this is not all doom and gloom but in fact opportunity and the chance to bring innovative medicines to the pyramid of wealth or incomes that exist in such markets. What is even more certain is that future Industrial Pharmacists will need to have a broader skill set
which is compatible with this global world. The emphasis will be on communication skills, developing a management and leadership capability, and the ability to influence people, projects and resources often as a matrix leader will be of vital importance. Due to the changing environment in which we now operate, EIPG (www.eipg.eu) has continued to make Education one of our key strategic priorities for 2010 and beyond. At the General Assembly of the EIPG to be held in Milan between May 15th/16th how Pharmacists will be educated and the future skills required will be reviewed by a dedicated workstream led by Great Britain, France and in conjunction with Pharmine (Pharmacy Education In Europe: www.pharmine.org). Our desire is such that a Pharmacist upon qualification can pursue a career in Industry, Academia, Community or Hospital, thus reinforcing the benefits of this polyvalent professional qualification.
In addition, the EIPG will continue to champion the cause of the Qualified Person, the fight against counterfeit medicine and the need for secure supply chains. Of particular importance is understanding the needs and challenges associated with Cold Supply Chain as more and more companies are developing product portfolios consisting of a greater proportion of biological products. I would urge you to visit our website (www.eipg.eu) as we regularly update it with guidance documents and interesting news items. I would like to thank Dr Claude Farrugia for his dedication and support in this respect. With very best wishes
Gino Martini FRPharmS President, EIPG
gmp-review news free news service for gmp revıew subscribers Monthly news service will keep you up-to-date on new developments in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers. Subscribers should contact subs@euromed.uk.com to register european INDUSTRIAL PHARMACY • Issue 5 February 2010
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EIPG GUIDANCE ON CPD FOR REGULATORY AFFAIRS by EIPG* Introduction
M
aintaining competence throughout a career during which new and challenging professional responsibilities will be encountered is a fundamental ethical obligation for all those working in the pharmaceutical industry.
L
e développement professionnel continu associe différentes techniques et méthodes pour maintenir et développer de façon continue les connaissances et qualités personnelles nécessaires pour assurer une fonction. C’est un processus permanent qui permet à une personne d’assumer les responsabilités nécessaires pour son développement personnel et professionnel. This is particularly important for the regulatory affairs (RA) professional as there is now a broad range of technical, strategic and managerial regulatory roles as well as many new opportunities for regulatory professionals to become involved with different types of companies in the pharmaceutical industry. EIPG has recognised this personal responsibility and has developed a Guidance to provide RA professionals with a more systematic way to analyse and review the development needs to meet their own personal responsibility obligation and career development and also of their staff. All of this can be achieved by undertaking Continuing Professional Development (CPD), a tool used to demonstrate an individual’s ability to perform in a role as well as being used to further career development. What are the benefits of CPD for the individual?
* Report by EIPG Regulatory Affairs members from France, Germany and UK.
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It will provide RA professionals with a more systematic way to analyse and review the development needs of their staff.
Employers and clients of contract/consulting companies will particularly value RA professionals who have a commitment to CPD. RA professionals who adhere to the principle of CPD will be more valued by their employers. The collaboration of the company the RA professionals is working for is very important, in order to get training courses. A positive evaluation after CPD activities also helps to motivate the RA personnel. The growing CPD record will form an invaluable part of the Curriculum Vitae (CV) of the RA professional and it is therefore in their interest to keep this record up to date. What is CPD?
CPD includes attending formal in-house or external training courses or workshops but is also a much broader concept which includes the following: Being mentored by a more senior colleague in some new aspect of regulatory work; Consulting the Internet for new or existing information and guidelines from the regulatory agencies on procedures, technical requirements for filings, etc.: ♦ Consulting the Internet for regulatory
intelligence (eg. precedents from other companies’ submissions and approvals); ♦ Reading technical and professional
publications (e.g. TOPRA Regulatory Rapporteur); ♦ Reading books and articles about “soft
skills” (eg. influencing, decisionmaking, negotiations) and management; ♦ Preparation of presentations; ♦ Preparation of publications; learning;
Work-based projects and short term role/department attachments; Non work-related activities such as voluntary work or coaching a team, etc. especially when working on interpersonal or leadership skill areas: ♦ Attending industry or agency working
party meetings; ♦ Being coached.
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E I P G G U I DA N C E O N C O N T I N U O U S P R O F E S S I O N A L D E V E L O P M E N T ( C on t . ) The five step cyclical process for CPD
CPD must be an ongoing cyclical process of continuous improvement, in which the RA professionals seek to improve and maintain their technical knowledge and personal qualities for the current and any future roles. CPD is not just Continuing Education (CE) although this can have an important role in fulfilling CPD needs. A structured CPD programme must be actively managed to be effective and may include the following five steps (see Figure 1) . Self appraisal
The identification of CPD needs may arise from one or more of the following: ♦ Personal assessment of
performance ♦ Performance review by
professional/peer ♦ Professional/company
requirement for keeping current ♦ Career development for future
portfolio opportunities of the company or for a future role Personal plan
This identifies the resources and actions required to meet the personal CPD needs identified in step ♦ A whole list of options can be
identified. Examples of possible resources or actions are:
2 the chosen resource or action is undertaken. This could be in the form of: ♦ Mentoring/work-shadowing ♦ Training course(s) ♦ Professional qualifications ♦ Informal discussions with
colleagues ♦ Participation in professional body
working groups ♦ Reading and other research Documentation
For the reasons identified previously, it is important to document all CPD activities undertaken so that this can be provided as evidence of competence. Company records often merely consist of ‘training records’ so it is important that other types of CPD are systematically recorded. Some regulatory bodies or national professional bodies may require all aspects of appraisal, planning, action and evaluation to be systematically recorded and then made available for review and inspection. Others may simply require the CPD actions themselves to be recorded. Evaluation
Benefit from participation in any CPD activity should be evaluated. The professional RA should review in how much the action step has covered (or exceeded) the professional plan step. Possible questions to ask include: ♦ Were my needs addressed?
that is defined in the document but the relevant pieces to his/her job need to be defined and adhered to with this document as guidance. Gaining marketing authorisations for new drugs/ establishing the best regulatory strategy, new indications, etc.
It is the responsibility of the RA professional to establish a regulatory strategy assessment for all new drug product developments, preferably starting once pre-Phase 1 is initiated. This assessment will be a continuously evolving document that will be adapted and revised on a regular basis to include and address any new information and data gained. It takes into account the necessities and requirements of the non-clinical testing, the different clinical Phases including Phase I – III and the regulatory requirements to compile a complete marketing authorisation application dossier, which fulfils the current requirements. Consequently, the regulatory affairs professional has to ensure that any new guidelines and legislations are reflected in the assessment document and that appropriate actions are initiated at an appropriate timing. The assessment may also address particular needs of the different regions Europe, US and Japan (if applicable) and additional requirements of the rest-of-world countries.
Action
Regulatory affairs knowledge
These assessments will continue as part of the life-cycle management of existing drug products, i.e. it will include appropriate assessment of Phase IIIb and Phase IV studies for existing indications but also additional clinical and non-clinical development for new indications as well as pharmaceutical development activities to include new dosage forms or new strengths.
In this step the intentions of step 2 are brought into practice: from step
In general it cannot be expected that each RA professional knows all
The main emphasis needs to be put on optimising the regulatory
♦ Identification of possible training
course(s) ♦ Research into information/
literature/references to support ♦ Identification of colleague/peers
who could provide advice ♦ Previous work experiences
♦ Can I address what I learned? ♦ How will my work improve? ♦ What else can I do to support my
learning? ♦ This step also needs to be
documented properly.
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E I P G G U I DA N C E O N C O N T I N U O U S P R O F E S S I O N A L D E V E L O P M E N T ( C on t . ) strategy e.g. the choice of the approval procedure used, in order to improve the chances of success resulting in the best SmPC in the shortest amount of time. The advantages and potential disadvantages of an application via a centralized procedure vs. a decentralized / mutual recognition procedure in Europe have to be carefully evaluated including the choice of (co)-rapporteur and reference member states. The previous experiences gained from submissions of applications via different procedures is very important and the selection of the countries taking into account the needs of the company related to commercial issues has to be considered seriously also. The previous deficiency letters and answers provided in a dossier is a good way to learn the requirements form different countries and Agencies. The regulatory affairs professional will also ensure appropriate and adequate interaction with important regulatory authorities prior to submission of a new marketing authorisation application for new drug products or submission of a line extension. This may be done as part of scientific advice meetings or portfolio meetings. Communication and negotiations with Regulatory Agencies are important to keep in the documentation system for any Development Program. Maintaining existing authorisations
Responsibility for maintaining and updating existing authorisations includes preparation and submission of renewals of marketing authorisations, PSURshandling, preparation and submission of Variations (pharmaceutical variations, modification of the product information, extension of indication) and post marketing authorisation commitments.
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a) Renewals of marketing authorisation and PSURs-handling
Renewals of marketing authorisations and PSURs submission should be carefully planned for the whole portfolio of the pharmaceutical company, with yearly check if any amendment to the planning is needed. Renewals and PSURs are closely linked (but independent processes) and renewal submission dates can, in some cases, be amended in order to comply with the PSURs submission date. b) Variations
As part of life cycle management, changes to the Marketing Authorisation will be required. The extent to which variations will be needed, especially in terms of the quality information provided (CMC section), relates directly to the level of detail originally submitted as part of the Marketing Authorisation submission. It is the responsibility of the RA professional to assess the need for variations and advise on the supporting documentation needed as well as the best strategy for submitting them. c) Post marketing authorisation commitments
Activities related to post marketing studies must be carried out in compliance with, and reported according to, existing legislation. Regulatory affairs departments must have an updated knowledge of: ♦ Post-Authorisation Guidance ♦ Regulations regarding:
– Management of Post-approval Commitments of a Marketing Authorisation – Specific Obligations and Followup Measures for the Management of the Marketing Authorisation Regulatory affairs professional must also have a thorough understanding of the studies requested and must follow-up regularly their progress with the other departments
involved to make sure that the commitments of the company will be fulfilled. Note: Line extensions are sometimes considered as part of the life-cycle management; as they need a separate Marketing Authorisation, a new registration file need to be submitted. Regulatory intelligence
Regulatory legislation is continuously changing in order to reflect the current knowledge and scientific advances. Consequently, it is essential for the RA professional to keep current in terms of regulatory documents such as guidelines and legislation. In addition, it is vitally important to also track any discussion on anticipated changes, which are presented as concept papers via the websites of the European Medicines Agency (EMEA), the International Conference on Harmonisation (ICH) or the US Food and Drug Administration (FDA). It is vital to regularly check the official announcements of the different regulatory institutions, such as the websites of the EMEA, the ECCommission, the Head of Agencies for Europe and, when relevant, the respective websites of the national Health Authorities and Agency in the US etc. on a very frequent basis. Since upcoming changes in the regulatory environment can be of major impact on the regulatory activities for the approval process and the life-cycle management of medicinal products, continuous evaluation of newly published guidelines, etc. is of great importance and is one of the major tasks of a RA professional. In addition, pharmaceutical companies should be encouraged to contribute to the work of pharmaceutical associations on a national and a European level in order to position their view of any planned regulatory changes. This is
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E I P G G U I DA N C E O N C O N T I N U O U S P R O F E S S I O N A L D E V E L O P M E N T ( C on t . ) of importance to increase the visibility of the pharmaceutical industry in the issue and revision of regulatory documents. A good documentation system should be maintained regarding update legislation and guidelines from all sources from EU, US, etc., in addition, preferably a part of the regulatory affairs department works in the research of this subject including its regular updates. It is not only the RA professional who has to be up-to-date in terms of any anticipated and proposed changes in the regulatory environment but it is also his duty to keep his colleagues in adjacent departments informed of any relevant changes in the regulatory environment. It is his responsibility to evaluate the potential impact of regulatory guidelines and legislation on the company’s portfolio and initiate appropriate activities within the company. Within the scope of this “regulatory intelligence” he will be responsible to update his colleagues on a regular basis by issuing a regulatory newsletter and / or offering regular training sessions. This responsibility is not only limited with regard to the colleagues of the site but especially applies to colleagues from other subsidiaries and the headquarters when located in different countries in terms of globally acting pharmaceutical companies. Especially for those companies a functioning and powerful system for continuous exchange of information on changes is of vital importance. Archiving and tracking systems
Regulatory affairs departments have the responsibility to keep appropriate archiving and tracking systems to ensure traceability and appropriate timing of all regulatory activities.
a) Responsibility for keeping appropriate archiving
Regulatory affairs departments have to manage many documents (registration dossier, renewals, variations and amendments of the relevant part of the Marketing Authorisation dossier, change of SmPC/PIL, PSURs, requests from the health authorities and the answers submitted, regulatory texts). Regulatory affairs departments must ensure full traceability of all the documents and the date of submission, approvals etc. and a clear archiving system. This may best be achieved by help of a commercially available electronic document management system, however each regulatory affairs
given hereafter. However, these activities are not always under the responsibility of the RA professional, depending on the company structure and organization. a) Promotional material
In order to ensure the regulatory control of the advertising material, Regulatory affairs departments should have current knowledge of local regulations and health codes on advertising materials, on clinical trial methodology and interpretation of their results and should benchmark remarks or sanctions published by the health authorities or selfregulation industry bodies on other products to gain intelligence. b) Pricing and reimbursement dossier
b) Responsibility for keeping tracking systems
In some organisations, the Regulatory affairs department can be deeply involved in obtaining the most optimised price and reimbursement arrangements. Knowledge of the content of the dossier, of the key
Regulatory affairs departments have to anticipate and schedule many activities with mandatory timing such as renewals and PSURs Submission, answers to health authorities during a registration, variation or renewal procedure, submission of study results when they are part of the post-marketing follow-up measures etc.
parameters to put forward, in clinical trial methodology and interpretation of their results and in assessment criteria and Submission deadlines and Procedural timetables from the relevant health authorities is needed. Benchmark data on pricing and reimbursement for other products can be invaluable to gain expertise and understanding.
Additional knowledge elements
c) Clinical trial applications
department can have their own tracking and archiving system adapted to the structure of the company and to the portfolio.
Regulatory affairs departments have the responsibility for ensuring the compliance of the relevant company’s activities to the local and global regulations. Depending on the structure of the company (headquarter or affiliate), its size, the local regulations, regulatory affairs departments can be responsible for and have current knowledge and thorough understanding in the activities described hereafter. A short description of the field of activities that might be concerned is
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In most organisations, the Regulatory affairs department is responsible for the submission, follow-up and update of clinical trial application to the competent authorities. d) Labelling requirements
Regulatory affairs departments are responsible for ensuring compliance of the packaging materials of marketed products with the current regulations. Thorough knowledge of regulations and guidelines includes:
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E I P G G U I DA N C E O N C O N T I N U O U S P R O F E S S I O N A L D E V E L O P M E N T ( C on t . ) ♦ labelling requirements, ♦ excipients in the Label and
Package leaflet ♦ consultations with target patient
groups for assessment of the readability of the package leaflet, ♦ QRD templates when relevant e) Quality assurance and regulatory compliance
Regulatory affairs departments can be in charge of compliance and quality management systems for all the regulatory activities under its responsibilities. Knowledge is needed in writing procedures, training the regulatory staff on the procedure and training the other department staffs to some cross-departmental procedures, when relevant performing selfinspection or audit. f) Scientific information
According to the structure of the pharmaceutical company, regulatory affairs departments can be in charge of scientific information for all or part of the portfolio. Knowledge is needed in the preclinical and clinical development, in the scientific data available on the concerned products and in the relevant therapeutic area. g) Pharmacovigilance
Regulatory Affairs Department works in close collaboration with the Drug Safety department and the Qualified Person for Pharmacovigilance, in
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order to establish renewal and PSURs planning on a yearly basis for each product and collect all the information needed for their submission, also taking into consideration post-approval commitments or follow-up measures. In some organisations, the Regulatory Affairs professional is also the Qualified Person for Pharmacovigilance (QPPV). h) Communication, negotiation
Due to the multidisciplinary activities under the responsibility of the regulatory affairs department, close relationship with almost all the other departments (pre-clinical, medical, drug safety, pharmacovigilance, production, quality control, quality assurance, medical services, marketing and sales etc.) is needed and requires appropriate negotiating and project management soft skills. Skills and knowledge for communication and communicating information to other departments, Competent Authorities, Professional Associations are a key parameter in terms of compliance with regulatory requirements, lobbying, negotiation and effective relationship with external bodies. In addition, one of the major requisites of a RA professional is his project management competence in organising a large number of different projects and tasks at the
same time while ensuring the appropriate timing of the respective tasks according to the regulatory deadlines. Since the RA professional depends on the input of the various disciplines within the company such as clinical, non-clinical, marketing etc., his communicational and administrative skills should be rather distinct. i) Others
Many other knowledge elements might be needed according to the portfolio of the pharmaceutical company and the kind of regulatory activities performed by the relevant regulatory affairs department such as knowledge in compassionate use regulation, import/export regulation, paediatric regulation, Cell therapy and tissue engineering, Vaccines, Biosimilars, Gene Therapy, Pharmacogenomics, herbal medicinal products, OTC drugs, etc. Acknowledgement
Valérie LACAMOIRE, Conseil Central de la section B de l’Ordre des Pharmaciens Kelsey MOWER, Industrial Pharmacists Group, Royal Pharmaceutical Society of Great Britain (RPSGB) Ursula SCHICKEL, Fachgruppe der Apotheker in Wissenschaft, Industrie und Verwaltung have elaborated this continuing professional development in Regulatory Affairs guidance.
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PHARMACY EDUCATION IN HUNGARY by Sylvia Marton
H
ungary has nearly 10 million inhabitants and about 8,200 pharmacists. There are 2,394 community pharmacies, most of them having been privatised in 1990, or founded later and there are 129 institutes of pharmacies. Pharmacy education has a long history and great traditions. Every year 1,500 students attend the four faculties, and 300 students complete their studies. History of education
Pharmacy education in Hungary takes place in four places: Budapest and Szeged are the ancient, traditional ones, universities founded there more than 250 years ago, Debrecen and Pécs are newer, the faculty and school being established at the beginning of the 20th century. Graduate education belongs to the Ministry of Education, postgraduate education is governed by the Ministry of Health. The structure of education is multilevel, some subjects of basic sciences are provided by departments of other universities. Specialised pharmaceutical subjects are taught at departments belonging to the faculties. The tasks of faculties were always two dimensional: education and research. Among Semmelweis (university at Budapest) alumni there are a number of Nobel prize winners. Graduate education
DR SYLVIA MARTON is a Full Professor at the Department of Pharmacy, Semmelweiss University, Budapest, Hungary. The Department has co-operated with a number of pharmaceutical companies in Hungary and other European countries in the fields of research and/or education.
The faculties admit students after a successful entrance examination in two general subjects (Biology and Physics or Chemistry), nowadays combined with matriculation. Every year nearly 300 students start their studies in all four faculties according to a given quota determined by the ministry; foreign students have to pay for their education. Training is given in Hungarian and in English, the latter only for foreign students. The curriculum includes five years of basic and special studies. The first two
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years cover basic sciences and are taught outside the Pharmacy faculties. In the next three years emphasis is given to specialised knowledge in pharmaceutical and medicinal fields. Three elective subjects have to be selected in the ninth semester from more than 25 different topics. Types of training involve lectures (48%), seminars (3%) and practice (50%) which are evaluated after oral or written tests. Students must then write a thesis under the instructions of a tutor and defend it before the final exam. One month’s compulsory summer practice after years 2, 3 and 4 has to be given in a public or institutional pharmacy or within industry. Before and during the 10th semester the students have to spend 2+4 months in a practical training programme (min. 18 weeks in a community pharmacy and the rest in a hospital pharmacy). The final exam includes a written test, practical work and a theoretical part, the last two being given before a general board. On successful completion of their studies, they get their diploma which leads to the degree of Master of Sciences. 2009 was the first time pharmacists were given a doctor’s title, which is not a scientific one, but gives them the right to use “Dr” before their name. Postgraduate education
There are two main fields for pharmacists to get further education after getting their diploma: 1. Specialisation of pharmacists, 2. doctoral programs. All pharmacists who work on fields where they must renew their registration every 5 years, have to take part in continuing education (CE) or Life Long Learning (LLL) and collect a prescribed number of points. For all other pharmacists it is not obligatory. Specialisation
The Central Probational System in postgraduate training started in 2000 and circumstances and requirements are fixed in laws. Training is a residency type programme, involves 2 years of residency time common in all areas and one to three years plus special training in a selected field. Fifteen special areas now exist, but the system is now under
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PHARMAC Y EDUC ATION IN HUNGARY (Cont.)
➞
➞
Medical Treatment
➞
Fields of Education
➞
➞
Research Experience
➞
➞
Fundamental Activity
Research Area
Figure. Education and Research, 2-dimensional tasks of the university faculties.
revision. Those specialising during their residency time belong to one of the faculties. Practice is given in accredited community pharmacies, hospitals, industrial companies and other healthcare facilities. On finishing their studies, examination is before a national committee whose members are delegated by Ministry of Health. Two years ago the financial status was changed. Previously, places were determined by the Ministry of Health, which also provided financial backing. The applicant now has to pay a tuition fee, depending on the faculty. Doctoral programmes
Doctoral Schools as part of the universities lead the education of PhD students. The degree is a worldwide recognised qualification. Three forms of education exists: full time students (with scholarship), parttime students (employed by industry, research institutes etc.), individual students (with great experience, doing their work alone, and entering into
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collected in three main categories: 1. obligatory courses (organised only by universities) (50 points per 5 years), 2. obligatory elected courses (hosted by universities) (25 points per 5 years),
➠
➞
Research
Training courses
➠
➠
➞
Education
➠
U N I V E R S I T Y
qualification phase without time limit). Beside theoretical courses students do practical research governed by their tutor. The candidate demonstrates their scientific activity with articles published (or accepted for publication) in international scientific journals and a written thesis. The doctoral examination is a public demonstration before a committee and an audience, where opponents also give their remarks. The committee decide on offering a PhD degree by confidential voting, based on written dissertation and the results of an oral presentation. Continuing education
The system has operated from year 2000, within a legal framework. Pharmacists working in public and hospital pharmacies are required to collect 250 points every 5 years. The points are of two types: practical and theoretical. The number of practical points is 100 (20 p.a.) and are given when somebody works full or part time. The theoretical scores (150 per 5 years) have to be
3. freely elected courses (the rest of theoretical points). The types of courses include: congresses, conferences, training courses, individual training course etc. Other opportunities to collect points include scientific publications, patents, giving lectures etc. When pharmacists specialise or get a PhD degree automatically get 50 points p.a. Distance learning is an individual category. The maximum number of points is limited (20 points p.a.) and one point is given after three questions are answered correctly. Answers are always checked by a competent committee. Education in Industrial Pharmacy
In graduate education, Industrial Pharmacy is not a separate obligatory subject. As a part of pharmaceutical technology, theoretical hours are given on fundamental operations, dosage forms prepared on an industrial scale (eg. aerosols, tablets, injections etc.), quality assurance, in the 7th and 8th semesters. Among practices, one third is pilot plant production of different dosage forms (involving tablets, infusions, ointments etc.), simulating the conditions in industry. One third is chemical control and one third is physical testing of base materials and end products (eg. stability tests, consistency determination etc.). Pharmaceutical technology as an obligatory subject occupies 19% of the total number of hours and takes four semesters. Students get acquainted with the small, middle and large scale preparation of drug
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PHARMAC Y EDUC ATION IN HUNGARY (Cont.) products. A separate, elective subject may be selected in the 9th semester by students interested in Industrial Pharmacy. Invited speakers from industry and ministry give lectures on research and development of dosage forms, quality assurance and validation. During specialisation, one of the areas involves pharmaceutical technology, including both small and large scale production of medicaments. A separate degree may be gained from quality assurance. In this case after getting the diploma, a further two years’ practice is needed before one gets permission to work alone. The use of the European Pharmacopoeia is obligatory in
Hungary. However, the Pharmacopoeia is not a separate subject but is incorporated into the appropriate compulsory subjects such as pharmaceutical technology, pharmaceutical chemistry and pharmaceutical administration. Conclusion
Pharmacy education in Hungary attempts to focus on patient demand rather than commerce. Reforms are needed in the graduate education system, with more emphasis on the problem solving ability of students and the quality control of education. It is necessary to follow-up pharmacists’ careers after getting their diploma. Postgraduate education has to be based on the requirements of employers.
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References 1. Antal I, Mátyus P, Marton S,Vincze Z. Developing the Pharmacy Curriculum in a Hungarian Faculty. Pharmacy Education, 2002; 1: 241–246. 2. Zalai K. Gyógyszerészképzés – a jövő gyógyszerészetének szolgálatában? (Pharmacy education – in service of future pharmaceutics?). Gyógyszerészi Hírlap (Pharmaceutical Journal), 2009; 20: 4–8. 3. 52/2003. (VIII. 22.) ESzCsM rendelet (Decree of Ministry of Healthcare) az orvosok, fogorvosok, gyógyszerészek és klinikai szakpszichológusok folyamatos továbbképzéséről (Order on the continuing education of physicians, pharmacists and clinical psychiatrist) 4. 66/1999. (XII. 25.) EüM rendelet (Decree of Ministry of Healthcare) a szakorvos, szakfogorvos, szakgyógyszerész és klinikai szakpszichológus szakképesítés megszerzésérol (Order on the specialisation of physicians, pharmacists and clinical psychiatrist) 5. 42/2007. (IX. 19.) EüM rendelet a szakorvos, szakfogorvos, szakgyógyszerész és klinikai szakpszichológus szakképesítés egszerzéséről szóló 66/1999. (XII. 25.) EüM rendelet módosításáról (Modification of 66/1999. (XII. 25.) EüM Decree)
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SURFACE ANALYSIS EXPOSES COUNTERFEIT MEDICINES by Justine Bentley
S
urface Analysis is assisting the pharmaceutical industry in a number of ways, including for example the optimisation and acceleration of new product development, evaluation of product and packaging stability, rapid identification of trace contamination and quality assessment of new manufacturing processes. And it is certain that Surface Analysis can illuminate much more about processes, and even origins, in this sophisticated marketplace – including helping detect counterfeits. Surface Analysis technology
Developments at the forefront of Surface Analysis technology are so powerful that it is enabling an independent UK research centre to materially assist pharmaceutical companies in their battle against counterfeit drugs. Not only does this technology – the latest in X-ray Photoelectron Spectroscopy (XPS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToFSIMS)in particular – afford a means of analysing the composition of various pharmaceuticals, recent work has also shown that it can even determine differences in the manufacturing processes involved, enabling the identification of previously undetectable chemical copies. Traditionally, one thinks of Surface Analysis as being concerned principally with the physical properties of surfaces – flatness, roughness, colour, reflectivity and so on. The state-of-the-art in this area is ‘3D non-contact profiling’, where white light interferometry techniques allow examination of ‘micro features’. Areas from a few square microns up to the centimetre scale can be analysed with nanometre resolution. JUSTINE BENTLEY PhD, is Technical Sales Consultant of CERAM, UK. email: justine.bentley@ceram.com
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Beyond bulk analysis
However Surface Analysis also looks at chemical composition – and the leading edge technology here is Secondary Ion
Mass Spectrometry (SIMS) which examines the chemical composition of surfaces and sub-surfaces, using a depth profiling technique to look at how this varies below the surface, to a depth of several microns using continuous bombardment. In fact, the word ‘surface’ is now almost misleading – the technology can now look at the chemical composition of small samples of all kinds of solids, by examining ions emitted from the surface. These techniques do not displace conventional chemical analysis. If somebody needs to discover whether a tablet is a genuine paracetamol tablet – or just a piece of chalk in fancy packaging – then bulk analysis (for example, Liquid Chromatography Mass Spectrometry) could be utilised. But if the counterfeit is more subtle, then bulk analysis may fail. It could be, for example, that the chemical composition appears correct, but the active drug distribution is incorrect. This is not just a matter of protecting patents, but in also protecting patients, for whom the counterfeit drug may not work effectively. For example, there are factors such as trace contaminants or distribution of the active components within the tablet – which could for example, change the rate of absorption and constitute a potential hazard to the user. Counterfeiting is a major problem not only for the pharmaceutical industry itself, but for the health of the world population in general. If people are taking pharmaceuticals other than those which have been fully tested and are properly licensed, there are obvious dangers, which in some cases could be extremely serious. Costly counterfeits
Counterfeiting was first officially recognised by the World Health Organisation (WHO) in 1985, which currently estimates that sales of counterfeit drugs worldwide may amount to 10% of the global supply, and sales could reach a staggering $75 billion by the year 2010. In 2006, the trade in the USA alone (with one of the most stringent pharmaceutical control regimes) was estimated at more than $30 billion. The pharmaceutical industry as a whole
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SURFACE ANALYSIS EXPOSES COUNTERFEI T MEDI CINES (C ont.) needs to be able to detect counterfeits, to protect its own reputation as well as its commercial interests. Many pharmaceutical companies now regularly turn to Surface Analysis techniques – not only for the detection of fakes, but for routine detailed analysis as part of a long-term quality assurance process. For example, CERAM has recently been involved in analysing the appearance of crystallite contamination in a drug formulation after storage; discovering the cause of tablet yellowing with age by investigating the leaching from packaging to product in long-term storage (Figure 1); mapping active drug distribution in controlledrelease products (including medical devices such as ‘stents’ with active drug coatings); analysing trace crosscontamination between production lines, and so on. As pharmaceutical technology is continually moving forward, research is constantly exposing new techniques for analysis and monitoring. One pharmaceutical manufacturer approached CERAM with an unusual problem – to which, at the time, nobody knew the answer – but it was thought that Surface Analysis might indicate a way forward. The question posed by the drug manufacturer was: “Suppose we have encountered a counterfeit medicine, in tablet form, whose chemical composition appears to be correct but whose method of manufacture is different from the path licensed for the drug. Is it possible to detect that difference using Surface Analysis techniques? ”We should note here that drug manufacture by other than the licensed process is just as much of an infringement as using the wrong ingredients –and because such manufacture is not properly authorised, health hazards could potentially arise.
Figure 1. ToFSIMS spectra of a yellowed tablet, enabling the cause of discolouration to be identified and corrected.
What the manufacturer wanted to investigate was the way that tablets are formed. Here it was using a technique called ‘direct compression’ – the active pharmaceutical ingredient (API) and other excipients are pressed together in a specific ratio to give the correct dosage. Another common method is ‘wet granulation’ where granules are formed in a wet process (requiring subsequent drying) before compression. Samples of tablets were prepared by the two different methods and offered for analysis. Techniques used
The primary analysis techniques used in the trial were X-ray Photoelectron Spectroscopy (XPS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToFSIMS). Both are high-vacuum technologies,
european INDUSTRIAL PHARMACY • Issue 5 February 2010
where the tablets were carefully sectioned in a controlled atmosphere to expose an inner surface. Using soft X-rays to dislodge photoelectrons from the surface of the target material, whose characteristic energies can then be detected, XPS can probe the surface of a material and determine the elements present, their concentrations and the chemical states of the elements found. This non-destructive quantitative testing method can detect elements down to 0.1At% concentration (Atomic percent: the ratio of atoms of a particular element to all atoms in a given volume). Every element can be detected (except hydrogen and helium) with a sampling depth of typically 5-8nm. ToFSIMS uses a primary focused ion beam to bring about a collision
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SURFACE ANALYSIS EXPOSES COUNTERFEI T MEDI CINES (C ont.)
Silica Core
Drug Molecular Ion
Si+
[M+H]+ m/z 288
Ethylcellulose Film Coating
Overlay
C3H7O+
Figure 2. Cross-section of the tablet whose manufacturing process was being deduced. (Left) the optical image by conventional microscopy, and (right) images generated in the ToFSIMS investigation.
cascade, causing secondary ions to be emitted from the surface of the target material. The ‘time of flight’ of these ions to the detector is related to their mass. This gives information regarding elements, functional groups, polymer groups and molecules. Unlike XPS, the technique is not quantitative, but does provide more detailed structural information, particularly for organic and polymeric components. The principal technologies
Spectral ToFSIMS provides detailed molecular information from the outer 1-2nm of a surface whilst spectral XPS provides quantified elemental and oxidation-state information from the outer 5-8nm with a sensitivity of 0.1At%. Both techniques can be utilised in imaging mode.
With very low primary ion doses, samples can be analysed with effectively no damage to the surface
14
under examination, with a sampling depth of 1-2nm and detection sensitivity in the parts-per-million to parts-per-billion range. The surface under examination can be analysed to produce a colourcoded chemical map, then full spectra can be obtained for every pixel point within the image. Distribution of pressing lubricant
The initial study indicated that the distribution of ‘lubricant’ might well be a parameter which could help identify the manufacturing process. Lubricants of some sort are used in most tablet formulations, the commonest being magnesium stearate. This is readily detectable by both XPS and ToFSIMS. It was postulated that the distribution of lubricant may be different in tablets produced by the two manufacturing processes – in wet granulation, the lubricant is added prior to compression and coats the surface of the granule (ie. extra granular) but direct compression mixes the lubricant powder directly with the other
ingredients, and it could be that the lubricant is more evenly distributed across the tablet as a result. In the event, when comparisons were drawn, changes in the surface composition and distribution became clearly identifiable (see Figure 2). By pinpointing key indicators such as these a complex model was produced, which proved very effective at differentiating between tablets produced using direct compression or wet granulation techniques.1 These are non-trivial results – it so happens that most pharmaceuticals are administered in tablet form, and of these, a considerable number are produced using magnesium stearate as the pressing lubricant. It is evident that this technique could shed light on the manufacturing processes involved in the production of many of them. What this study has shown, however, is that Surface Analysis technology is able to probe into the method of manufacture of tabletted preparations, even where a bulk chemical analysis can find no differences between the genuine and the copy. It is certain that Surface Analysis can discover even more about the nature and origins of counterfeit pharmaceuticals, to say nothing of helping to ensure the purity and quality of genuine ones. CERAM remains at the forefront of this research. References 1. Drug Development and Industrial Pharmacy, 32: 253–261, 2006.
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CHONDROCELECT THE FIRST ADVANCED THERAPY MEDICINAL PRODUCT IN EUROPE by Tom Sam
M
ore than 2 million articular cartilage defects are diagnosed each year with approx. 130,000 serious full thickness defects. ChondroCelect is a new, tissue engineered product intended to be used in patients having damaged cartilage, for instance caused by a sports incident. The product is intended to repair damaged cartilage thereby avoiding joint problems causing arthrosis, for which an “artificial knee” or prothesis often is the only solution. ChondroCelect is the first product to benefit from Europe’s new legal and regulatory framework for Advanced Therapy Medicinal Products (ATMP), regulation (EC) 1394/2007. The product recommended by European Medicines Agency (EMEA) to be approved by the European Commission is an autologous cell-based medicine used to regenerate cartilage at the end of the thighbone in the knee. It consists of cartilage-forming cells, the so-called chondrocytes, taken from a healthy region of the patient’s cartilage, grown outside the body, and then re-implanted by surgery. The product utilises marker proteins predictive of the capacity of the expanded human articular chondrocytes to form stable cartilage in vivo. ChondroCelect is a tissue engineered product. This type of ATMP contains cells or tissues that have been ‘engineered’ to repair, regenerate or replace tissue. Another example of a tissue engineered product is artificial skin, which is used to treat patients with burns. Other ATMPs
TOM SAM PhD is Senior Director Global Regulatory Affairs, Schering-Plough, The Netherlands email: tom.sam@spcorp.com
The Regulation recognizes two other types of products as ATMPs, somatic cell therapy products and gene therapy products. Somatic cell therapy products contain cells or tissues that have been manipulated to change their biological
european INDUSTRIAL PHARMACY • Issue 5 February 2010
characteristics. They can be used to cure, diagnose or prevent a disease. An example of somatic cell therapy is the use of a patient’s manipulated cancer cells to fight remaining cancer cells in their body. Also, stem cell therapy will be regulated as an ATMP. Gene therapy products are intended to treat genetic diseases. When the new gene is integrated into the cell’s chromosomes, the cell produces or stops the production of a protein, with the aim to slow down or cure a disease. Committee for Advanced Therapies
The regulation establishes within the European Medicines Agency a new committee, the Committee for Advanced Therapies (CAT). The CAT brings together scientific expertise in advanced therapies from across the European Union. The legislation requires that the expertise within the Committee covers all the areas relevant to advanced therapies, including medical devices, tissue engineering, gene therapy, cell therapy, biotechnology, surgery, pharmacovigilance, risk management and ethics. The CAT prepares a draft opinion on the quality, safety and efficacy of each ATMP that is submitted for evaluation to be sent to the Committee for Medicinal Products for Human Use (CHMP), the committee responsible for human medicines at the EMEA. Incentives
Currently, advanced therapies are often developed by small companies or by research units in hospitals. The new legislation provides scientific and financial incentives to help these smaller companies and units to continue their advanced therapy R&D programmes. In case of ChondroCelect, the product has been developed by TiGenix NV, a latestage biomedical company, founded in 2000 as a spin-off of the Universities of Leuven and Gent, focusing on regenerative medicine and orthobiologics for the innovative local treatment of damaged and osteoarthritic joints. Small and medium-sized companies like TiGenix developing advanced therapy medicinal products can obtain reductions in the fees payable to the EMEA. The
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C HO N D R O C E L E C T ( C o n t . ) June 2009 the recommendation that ChondroCelect be granted marketing authorisation. As part of the application, the CAT and the CHMP requested TiGenix to submit a risk management plan with a series of measures, including further studies to ensure that the medicine’s efficacy and safety are followed up in a robust manner once it is on the market. With the adoption of the scientific recommendation for ChondroCelect by the European Commission, Europe will not only have its first ATMP approved but also demonstrated, that it has a procedure in place capable of bringing these beneficial but complex products to the market, guaranteeing a high level of health protection for its patients. Figure: Mode of action of ChondroCelect, Europe’s first advanced therapy medicinal product (Figure adapted from TiGenix presentation dd. November 20, 2008)
EMEA also gives scientific support to help these companies design pharmacovigilance and risk management systems to monitor the safety of their ATMPs.
Marketing Authorisation granted
On the basis of the opinion from the CAT, the CHMP adopted on 25
gmp revıew
Further reading 1. A summary of opinion for ChondroCelect: http://www.emea.europa.eu/pdfs/human/o pinion/ChondroCelect_38336609en.pdf 2. An introduction at the EMEA website: http://www.emea.europa.eu/htms/human/ advanced_therapies/intro.htm 3. Regulatory Rapporteur Vol 6, No 7/8, July/August 2009 – focusing on ATMPs
the key to gmp
gmp revıew is the first newsletter dedicated to the analysis of international pharmaceutical regulations and providing informed comment on good manufacturing practice. Researched and edited by an expert team, gmp revıew will provide you with a clear, practical guide to the often complex and jargonridden regulations that are continually being produced. See our website for details or call +44 (0)1428 752222
www.euromed.uk.com 16
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IN SITU GEL-FORMING SYSTEMS FOR SUSTAINED OCULAR DRUG DELIVERY By Mahesh N Mali and Ashok A Hajare
I
n the development of ophthalmic products, drug delivery is one of the most challenging and difficult fields for investigators. The conventional formulations such as solutions, suspensions, ointments, etc. shows some constraints such as increased precorneal elimination, high variability in efficiency and blurred vision, respectively, which reduce their bioavailability. In situ activated gelforming systems are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form a viscoelastic gel in response to environmental changes such as change in temperature, pH and osmolarity. In the past few years, an impressive number of novel temperature, pH, and ion induced in situ gel-forming systems have been reported for sustain ophthalmic drug delivery. This review includes investigation of various temperature, pH and ion induced in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increase their bioavailability.
Introduction
ASHOK A HAJARE is Head of the Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy and Research Centre, Kolhapur, MS, India Email:aahajare@ rediffmail.com MAHESH N MALI is a research student at the same college
To improve ocular drug bioavailability, significant efforts are being directed towards new drug delivery systems for ophthalmic administration. The anatomy, physiology and biochemistry of the eye render it exquisitely impervious to foreign substances. Most ocular treatments call for topical administration of ophthalmically active drugs to the affected tissues. The basic ophthalmic solutions, suspensions and ointment dosage forms are clearly no longer sufficient to combat some presentday virulent diseases, especially in developing nations1. The development of new products for the treatment of ophthalmic diseases is facing a double challenge viz pharmacological and formulation factors. In addition, other problems are tolerability and comfort
european INDUSTRIAL PHARMACY • Issue 5 February 2010
Figure 1. Cross-section of eye.
requirements of the eye.2 In spite of active and continued research and the frequent introduction of novel ophthalmic drugs, delivery systems do not seem to progress at the rapid pace typical of oral, transdermal or transmucosal delivery. The vast majority of existing ocular delivery systems are still fairly primitive and inefficient.3 Whenever any ophthalmic formulation is applied topically to the anterior segment of the eye, only a small amount (~5%) of drug penetrates through the cornea and reaches the internal anterior portion of the eye to have any effect. The most commonly used ophthalmic dosage forms are simple, usually water-soluble drugs delivered topically in an aqueous solution4 and waterinsoluble drugs administered topically as an ointment or aqueous suspension. Anatomy and physiology of eye
An anatomical cross-section of the human eye (Figure 1) identifies the several ocular tissues for a better understanding of their functions and their involvement in selected ophthalmic disease, as well as to locate specific site of drug administration and action.5,6 Conventional dosage forms7
Medication is applied to the surface of the eye to treat infections such as conjunctivitis, blepharitis, keratitis sicca, etc. or to provide intraocular treatment through the cornea for diseases such as glaucoma. Conventional ophthalmic dosage forms with their benefits and constraints are listed in Table 1. Constraints to ocular drug delivery
The poor ophthalmic bioavailability is the result of ocular anatomical and
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I N S I T U S T I M U L I S E N S I T I V E G E L - F O R M I N G S Y S T E M S ( C on t . ) Table 1: Conventional ophthalmic dosage forms Dosage forms Benefits
Constraints
Solutions
Convenient
Rapid precorneal elimination. Loss of drug by drainage. Non-sustained action.
Suspensions
Patient compliance. Best for drug with slow dissolution.
Drug properties decide performance. Loss of both solution & suspended solid.
Emulsions
Prolonged release of drug from vehicle.
Blurred vision. Patient’s non-compliance. Possible oil entrapment.
Ointments
Flexibility in drug choice. Improved drug stability. Inhibition of dilution by tears. Resistance to nasolacrimal drainage.
Sticking of eyelids. Blurred vision. Poor patient compliance. Drug choice limited by partition coefficient.
Gels
Comfortable. Less blurred vision.
Matted eyelids after use. No rate control on diffusion.
physiological constraints. Ocular tissues are protected from various mechanisms: continuous tear secretion, an impermeable surface epithelium and a transport system actively clearing the retina. Physiological barriers to the diffusion and active absorption of topically applied ophthalmic drugs exist in the precorneal and corneal spaces.8 Precorneal constraints include solution drainage, lacrimation, tear dilution, tear turnover and conjuctival absorption. For appropriate bioavailability, a proper duration of contact with the cornea should be maintained.9 An instilled dose leaves the corneal area within 5 minutes of instillation in humans.10 The natural capacity of the conjunctival cul-de-sac is 7-10µl whereas an ophthalmic dropper delivers about 30µl.11 Lacrimation can be induced by many factors: drug entity, pH and tonicity of the dosage form.12 Formulation adjuvants can also stimulate tear secretion.13 Tear turnover acts to remove drug solution from the conjuctival cul-de-sac.
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Clearly, the physiological barriers to topical corneal absorption are formidable. The result is that the clinician is forced to recommend frequent high doses of drugs to achieve the desired therapeutic effect. This regimen not only results in extreme fluctuations in ocular drug concentration but may cause many local and/or systemic side effects. To solve these constraints and to improve bioavailability, various novel techniques have been developed such as the use of viscosity imparting agents, ocular penetration enhancers, corneal collagen shields, the design of drug delivery systems targeting the noncorneal route, ophthalmic inserts, ocular iontophoresis, using mucoadhesive polymers, aqueous gels, particulate systems viz microspheres and nanoparticles, vesicular systems viz liposomes, niosomes, pharmacosomes and discomes and last but not the least, in situ gel systems. All these techniques improve the bioavailability of ophthalmic formulations but some
of the formulations prepared by these techniques require the experts and some are not comfortable to the patients. Hence no one technique is superior. In situ gel systems
A more desirable dosage form would be one that can deliver drug in a solution form, create little to no problem of vision and need be dosed no more frequently than once or twice daily. In situ activated gelforming systems are those which are when exposed to physiological conditions will shift to a gel phase. This new concept of producing a gel in situ was suggested for the first time in the early 1980s. Gelation occurs via the cross-linking of polymer chains that can be achieved by covalent bond formation (chemical cross-linking) or non-covalent bond formation (physical cross-linking).14 The progress that has been made in gel technology is in the development of a droppable gel. In situ gel-forming systems can be described as low viscosity solutions that undergo phase transition in the conjunctival cul-de-sac to form viscoelastic gels due to conformational changes of polymers in response to the physiological environment.7, 15 The rate of in situ gel formation is important because between instillation in the eye and before a strong gel is formed, the solution or weak gel is produced by the fluid mechanism of the eye.16 Importance of in situ gel systems
The major importance is the possibility of administrating accurate and reproducible quantities compared to already formed gel. It is conveniently dropped as a solution into the conjunctival sac, enhancing patient compliance and minimizing interference with blinking. It increases the contact time of drug
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I N S I T U S T I M U L I S E N S I T I V E G E L - F O R M I N G S Y S T E M S ( C on t . ) with the mucus at the site of absorption and has better bioavailability.17 Mechanism of in situ hydrogels in sustained ophthalmic drug delivery7
Many mechanisms have been employed to cause reversible sol-gel phase transition, ie. in situ gel forming system by different environmental conditions. The stimuli that induces various responses to form hydrogels includes: physical stimuli such as change in temperature, electric fields, light, pressure, sound and magnetic fields; chemical stimuli such as change in pH and ion activation from biological fluids; and biological or biochemical stimuli such as change in glucose level. Out of these different environmental conditions only pH, ion activated and temperature stimuli are used for ophthalmic drug delivery. Temperature induced in situ gel systems
Gelling of the solution is triggered by change in temperature, thus sustaining the drug release. This can be achieved by using a polymer that is a solution at room temperature (<25°C) and a gel at body temperature.18 Thermosetting polymer poloxamer has been used for pilocarpine with significant increase of meiosis and can be used up to 20-30%. An increase in concentration of poloxamer increases contact time, increases elasticity of the gel and decreases the sol-gel transition temperature. Poloxomer has mucomimetic properties and optical clarity therefore it can be successfully used as a tear substitute. It can be used in combination with hyaluronic acid and Carbopol showing the highest meiotic response in man. Ocular bioavailability of pilocarpine can be increased more readily by altering both the rheological
characteristics of the delivery systems containing pluronic and by using a smaller dose volume. Carbopol (0.3%) and pluronic (14%) in combination shows a better retention of drugs than either alone. Miotic response of pilocarpine from xyloglucon and pluronic in situ was observed to be the same. Formulations containing 3% methyl cellulose and a low concentration of pluronic provided a potential delivery system with improved ocular bioavailability. The Gelrite gellan gum formulation is therapeutically efficacious and provides sustained release of drug over 8 hours. The gelation temperature of chondroitin 6sulfate-graft-poloxamer was dependent on the concentration and content of chondroitin 6-sulfate and found to be suitable for ciprofloxacin. Release rate of vitamin B12 is dependent on gel dissolution of pluronic-g-poly(acrylic acid). The system shows significant prolongation in the drug resident time and improved bioavailability. pH induced in situ gel systems
Gelling of the solution is triggered by a change in pH. At pH 4.4 the formulation is a free-running solution which undergoes coagulation when the pH is raised by the tear fluid to pH 7.4. The pH change of about 2.8 units after instillation of the formulation (pH 4.4) into the tear film leads to an almost instantaneous transformation of the highly fluid latex into a viscous gel.19 Cellulose acetate phthalate latex, cross-linked polyacrylic and derivatives of carbomers are used. Preliminary investigations of the pH sensitive latex system for ophthalmic administration began in the early 1980s. Ocular drug delivery system containing pilocarpine with pH sensitive polymer cellulose acetate phthalate latex showed significantly prolonged meiosis in rabbit. There is no
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concentration dependence and no significant difference in AUC between the different grades of Carbopol when used for pilocarpine nitrate. Carbopol has a greater release rate for ketorolac tromethamine and tropicamide than any other polymer. A Carbopol formulation has been shown to be therapeutically efficacious, stable, non irritant and provide sustained release of drug over 8 hours. When used for indomethacin it enhances the action and therapeutic efficacy over 8 hours. Hydroxy ethyl cellulose was found to increase viscosity and prolong diclofenac sodium release. This system is used as an in situ gelling vehicle to enhance the ocular bioavailability of pefloxacin mesylate. Osmotically induced in situ gel systems:
Gelling of the solution can also be triggered by a change in ionic strength. It is assumed that the rate of gelation depend on the osmotic gradient across the surface of the gel. It is therefore likely that the osmolality of the solution might have an influence on the rate of the solgel transition occurring in the eye. The aqueous polymer solution forms a clear gel in the presence of the mono or divalent cations typically found in the tear fluids. The electrolyte of the tear fluid and especially Na, Ca and Mg cations are particularly suited to initiate gelation of the polymer when instilled as a liquid solution in the conjunctival cul-de-sac.20 The osmotically induced polymer Gelrite showed improvement in the ocular absorption of timolol in the albino rabbit. Favourable results of Gelrite for timolol maleate were obtained in terms of peak and duration of activity in 45 patients. When used for fluorescein, the gel produced a two-fold increase of penetration. Using hypotonic solutions of Gelrite, the gel can remain in the human eye for 20 hours.
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I N S I T U S T I M U L I S E N S I T I V E G E L - F O R M I N G S Y S T E M S ( C on t . ) An in situ gelling alginate system is an excellent drug carrier for prolonged ophthalmic delivery of pilocarpine. Gatifloxacin has been formulated with sodium alginate and hydroxypropylmethyl cellulose as in situ gelling vehicle to enhance ocular bioavailability and patient compliance. The gatifloxacin and atenolol formulations with sodium alginate are therapeutically efficacious, stable, non irritant and provide sustained release of drug over 8 hours. Conclusion
The complications in eye formulation are mainly due to specific anatomical and physiological features. The development of in situ stimuli activated gel-forming systems for ophthalmic drug delivery provides one of the simplest forms of in situ stimuli activated gel-forming systems. It is preferred over the other systems as it can be administered in drop form and create significantly fewer problems with vision as well as having sustained release properties. Over
the last decades, an impressive number of novel stimuli sensitive in situ gel-forming solutions have been described in the literature. The choice of a particular system depends on its intrinsic properties and evidence of its therapeutic use. References 1. Meqi SA, Deshpande SG. Ocular drug delivery. In: NK. Jain (Ed.), Controlled and novel drug delivery, CBS Publishers, New Delhi, 2002, p. 82–84. 2. Wagh VD, Inamdar B, Samanta MK. Polymers used in ocular dosage form and drug delivery systems. Asian J Pharma. 2008; 12–17. 3. Lee VH, Robinson JR. Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol. 1986; 2: 67–108. 4. Lang JC. Ocular drug delivery conventional ocular formulations. Adv Drug Deliv Rev. 1995; 16: 39–43. 5. Sreeraj M, Ashim KM. Overview of ocular drug delivery. In: AK. Mitra (Ed.) Ophthalmic drug delivery systems. 2nd edition, 2003, 1–11. 6. Gokulgandhi MR, Modi DM, Parikh JR. In situ gel systems for ocular drug delivery: a Review. Drug Del Tech. 2007; 7: 30–37. 7. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems – Recent advances. Progress in retinal and eye research. 1998; 17: 33–58. 8. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop size and initial dosing frequency problems of topically applied ophthalmic drugs. J Pharm Sci 1974; 63: 333–338.
9. Chrai SS, Patton TF, Mehta A, Robinson JR. Lachrymal and instilled fluid dynamics in rabbit eyes. J Pharm Sci. 1973; 62: 1112–1121. 10. Sieg JW, Robinson JR. Mechanistic studies on transcorneal permeation of pilocarpine. J Pharm Sci. 1976; 65: 1816–1822. 11. Mishima S, Gasset A, Klyce SD, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966; 5: 264–276. 12. Conrad JM, Reay WA, Polcyn RE, Robinson JR. Influence of tonicity and pH on lacrimation and ocular drug bioavailability. J Parenter Drug Assoc. 1978; 32: 149–161. 13. Mitra AK, Mikkelson TJ. Ophthalmic solution buffer systems I. The effect of buffer concentration on the ocular absorption of pilocarpine. Int J Pharm. 1982; 10: 219. 14. Kaur IP, Kanwar M. Ocular preparation: the formulation approach. Drug Devel Indust Pharm. 2002; 28: 373. 15. Joshi A, Ding S, Himmelstein KJ. Reversible gelation composition and method of use. US Patent No. 5,252,318, October 12, 1993. 16. Calfrs J, Edsman K, Peterson R, Jornving K. Rheological evaluation of Gelrite in situ gels for ophthalmic use. Eur J Pharm Sci. 1998; 6: 113–119. 17. Calfrs J, Edsman K, Peterson R. Rheological evaluation of Poloxomer as an in situ gel for ophthalmic use. Eur J Pharm Sci. 1998; 6:105. 18. Wei G, Xu H, Ding PT, Li SM. Thermosetting gels with modulated gelation temperature for ophthalmic use: Rheological and gamma scintigraphic studies. J Contr Rel. 2002; 83: 65. 19. Ding S. Recent advances in ophthalmic drug delivery. Pharm Sci Technol Today. 1998; 1: 328–335. 20. Bheskaran S, Lakshmi PK, Harish CG. Topical ocular drug delivery: a review. Ind J Pharm Sci. 2005; 64: 404–408.
Industrial Pharmaceutical Microbiology Standards & Controls
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Looseleaf format Special supplements Regularly updated
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REGULATORY REVIEW
Review of major developments in GMP in the EU and USA, October 2009 to January 2010
by Steve Fairchild The last 3 months have seen the United States Food and Drug Administration provide further information about the more rigorous approach it has adopted recently to following-up GMP inspection findings and enforcing cGMP. Meanwhile European regulators have published a number of new and revised guidance documents along with proposals for revision of certain other guidance. Perhaps the most significant of these developments is the proposal to revise the Chapters of the EU GMP Guide that deal with contract manufacture and analysis. Last but not least, more information has been made available about GMP and GCP inspections in the UK. United States of America Changes to follow-up and enforcement procedures
The US Food and Drug Administration (FDA) has provided more details on how it is going to implement its earlier commitments to make the process for dealing with inspection findings more effective. This information is contained in a ”Notice”, spelling out how the FDA will assess responses to inspectional “observations”. An important feature of this is that in future companies will only have 15 working days from the completion of an inspection to make an initial response to the inspector’s observations (in the “Form 483”). Later responses will not be considered until the follow-up process has been completed. This tougher approach is due to be reviewed in 18 months’ time. The FDA is also making changes to the “Warning Letters” (WL) pages on its website. This involves weekly publication of recent WLs, inclusion of a corresponding close out date and close out “program” together
with updated information about the WL process. New and updated regulatory guidance
The FDA has issued revised regulatory guidance covering procedures for formal meetings between the FDA and sponsors of licence applications, for notifying the intent to use an accredited person for the “third party” inspection program for medical device manufacturers and for accreditation of persons involved in this program. The FDA has also published new draft guidance on dosage devices that accompany over-the-counter medicines. Proposed rule for the application of cGMP to combination products
The FDA has issued a “Proposed Rule” that will clarify how existing cGMP Regulations apply to products that consist of two or more “regulated products” (eg. a drug product and a medical device). Reduction in potency of heparin
The FDA has issued a general warning about a reduction in potency of products based on heparin following a reduction of approximately 10% in the potency specified for it in the United States Pharmacopeia. Europe Implementation of new legislation
The European Community has now completed the package of legislation that will regulate Advanced Therapy Medicinal Products (ATMP). Review of EU clinical trials (CT) regulations
The European Commission has launched a review of the operation of legislation introduced in the EU in 2001 covering clinical trials. This is set out in a consultation document that contains an
european INDUSTRIAL PHARMACY • Issue 5 February 2010
explanation of the current system of controls along with a number of questions about its operation. New and revised EU scientific guidelines
The European Medicines Agency (EMEA) has proposed what is likely to be a fundamental revision of Chapter 7 of Part I of the EU GMP Guide (Contract Manufacture and Analysis). The objectives, scope, timescale and other details of this review are set out in a recent Concept Paper from the EMEA. It is intended that this review will also include Part II of the EU GMP Guide. The EMEA has issued another concept paper for the revision of existing guidance on radio-pharmaceuticals that utilise monoclonal antibodies. Implementation of a risk based approach to inspections by the UK drug regulatory authority (MHRA)
The MHRA has published additional information on its website about its existing risk-based inspection programme for pharmaceutical manufacturers and distributors. It has also recently adopted a similar approach to the planning and execution of inspections of contract laboratories. Information on the implementation of clinical trials legislation in the UK
The MHRA has also published the first annual report on the GCP inspections it performed between 2007 and 2008. The content of the report includes the number of inspections together with the type and frequency of deficiencies found. 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
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NEWS FROM THE EIPG Bureau meeting in Brussels
T
he meeting format and agenda for the 2010 General Assembly on 15/16th May in Milan were drafted. Proposals will be put to the Assembly for the EIPG Statutes to be updated. It is to be recommended that the existing Bureau of president, 2 vicepresidents, delegate for external affairs and the secretary/treasurer be replaced with a Bureau membership of the president, treasurer and 4 vice-presidents ( with flexible job descriptions covering communications, education & careers, European affairs, training & professional development) This will add one extra Bureau member. The Bureau has remained unchanged since the foundation of EIPG in 1967 when there was half the number of members. European Commission
In November, the newly appointed Head of Unit 4, DG Internal Market was introduced to the European organisations of pharmacy. Representatives from the community and hospital pharmacists groups and EIPG met with Jurgen Tiedje and his pharmacist working on professional qualifications, Peter Mihok. Amongst the 800 regulated professions for which he is responsible, Mr Tiedje’s duties cover pharmaceutical education and the Professional Recognition Directive and we anticipate further constructive meetings.
December. Papers were presented on the development of new and updated GMP guidance documents, the role of the qualified person and the GMP provisions applying to atypical actives (chemicals used in much greater quantities in other industrial sectors than the pharmaceutical industry) Process validation, risk based scheduling of audits and melamine contamination were amongst other subjects discussed. It was agreed that EIPG would assist a Pharmaceutical Excipients Council (IPEC) working group in looking at the security of the medicines supply chain and preparing a white paper to be presented to the EMA. This would inform the Regulatory Authorities major re-drafting of the Good Distribution Practice document which is to include a section on falsification of medicines. Several chapters of the EU Guidelines to Good Manufacturing Practice are also being updated by the EMA Anyone interested in contributing to GMP updates or to the subject of supply chain security should contact Jane Nicholson at: jane@nicholj.plus.com and she will put you in touch with our working party members. EIPG Website
Warnings about counterfeit medicines from official sources will appear under the new heading of VigSim (Vigilance for Counterfeits). EMA launches new organisational structure
Interested parties meet at EMA in London
Piero Iamartino and John Jolley represented EIPG at the meeting of GMP/GDP Inspectors Working Group with interested parties on 2nd
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changes on 8 December 2009, with the launch of a new organisational structure and a new visual identity. Among the highlights of the new organisational structure is the integration of human pre- and postauthorisation activities into one unit, to guarantee seamless lifecycle-management of medicines. The creation of a new unit for patient health protection further strengthens the Agency’s focus on safety-monitoring of medicines. In addition, a dedicated group for the management of product data and documentation will improve the efficiency of data management processes throughout the Agency. Established in 1995, this is only the second time there has been a major re-organisation of the Agency’s services. The Agency’s responsibilities and tasks have grown, giving it a stronger role in the protection of public and animal health in Europe. The number of medicines the Agency is overseeing has increased, as has the complexity of procedures. All of this has been underpinned by the creation of additional scientific committees and advisory groups, which bring with them the need for enhanced coordination and support. Legislative proposals currently being considered by the European Parliament and Council are expected to bring further responsibilities to the Agency. In line with these changes, the Agency's website has a new address, www.ema.europa.eu, and Agency email addresses take the extension '@ema.europa.eu'. Jane Nicholson, Executive Director EIPG
The European Medicines Agency officially unveiled a package of
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PHARMACEUTICAL FORUM The following questions and responses are a selection of those published on an open online discussion group www.pharmweb.net/gmp.html. The Forum serves as a means of exchanging views on international regulations affecting the pharmaceutical industry. Readers are invited to contribute to the Forum. Where (or why) are companies going wrong?
Q
Most of my recent experience is in Europe but of course I follow the FDA warning letters. Over the last few months I am seeing 483s issued for such basic and primitive errors that makes me think that the companies involved, including large and reputable ones as well as small ones, have not opened the first book on GMP. Averaging of results, lost data, pencilled-in results, non-investigation and even release of OOS material. I can understand a company having a problem with computer compliance or a fine point as to water sampling loops but not these problems. Have we gone wrong somewhere? Is the concentration on such new issues as QbD and design space or PAT moved the goalposts at the expense of the basic traditional GMP?
Response 1 – I believe that as valuable as the
introduction of PAT (and other technologies) certainly is/will become in the time ahead – companies may just have taken their eyes off the ball as a consequence. Companies and senior technical managers must get back to basics with their manufacturing/development groups and where it is demonstrably clearly necessary, abandon those “business” hats many of them are obliged to wear in these troubled economic times and insist upon directing their senior professionals towards re-visiting and re-acquainting themselves with the basic requirements of GMP. All the fancy technology in the world cannot protect against that single critical human error brought about by overconfidence – and indeed over-familiarity – when dealing with the key quality critical GMP considerations that always must be given priority one.
Response 2 – I could not disagree with you more. I
spent sixteen years in the aviation industry, during which time QA and QC took over the whole industry and when incidents through faulty manufacture virtually disappeared. We stated to see year on year no incidents attributable to technological faults. As systems were automated the human input was reduced. Clever design made it more and more difficult for the remaining human input to jeopardise safety. However, until all the remaining human input is replaced by technology, muddled thought processes
can and will often fail to interact correctly with highly technical systems. Now after sixteen years in the pharmaceutical industry let me say that this industry is nowhere near the standard of compliance that is considered adequate in aviation. Were any auditor from the aviation industry to apply aviation standards during pharmaceutical audits, they would close most, if not all, pharmaceutical plants. Response 3 – What is needed is a simple
application of basic risk management (not the high level philosophy being pushed today with QbD etc). Risk is a combination of frequency of event times its impact. If a failed airplane part could cause a crash then you spend money on quality and back-up systems. If a tablet is going to have a slightly different release profile with no therapeutic consequence then maybe you shouldn’t be quite so concerned. I don’t think that anyone has any doubts that QA/QC is critical in the pharma industry but I do feel that some of the fundamentals are being neglected while concentrating on quality risk management. I personally have watched companies launch incredible complicated systems while the shop floor has drifted back to a level that I had thought and hoped we would never see again.
Response 4 – The questioner’s original comments
ring very true – the pharmaceutical industry still makes an extraordinary number of silly, simple, inexcusable mistakes when manufacturing drugs. Fortunately, few of these are serious enough to cause patient fatalities, but it is only a matter of time before we see the next “big one”. The comments regarding automation have, I suggest, missed a critical point. Automation will reduce, or even eliminate, human error, but only if the systems that are to be automated are fully and properly understood, reliable and robust. Aircraft stay in the air because the autopilot is programmed to manage the control of the aircraft within a set of parameters that are reliable and robust and fully properly understood by the system designers. I am amazed, though no longer surprised, as to how many manufacturing operations have little or no knowledge of the performance characteristics of their key processes – there’s no management of risk, or analysis to show whether the process and the critical parameters (if known) are in control or capable of meeting specification repeatably. It’s clear that the pharma industry hasn’t grasped the concept of a systematic approach to quality, but still treats it as a series of discrete activities, with too much focus on QC, not enough on QA.
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P H AR M A C E U T I C A L F O R U M ( C o n t . ) Response 5 – The previous comments on the aviation
industry are great for those highly-automated areas of work, such as water systems, integrated packaging lines, device assembly operations, etc. The bulk of what our manufacturing units do, however is little advanced from the work of the 18th century apothecaries: mixing, stirring, heating, cooling and so on. We still do considerable amounts of hand-packaging! The clever stuff happens in the medicinal chemistry labs, in the clinical study centres, in the marketing departments and (to some extent) in the API synthesis plants. You can have all the clever on-line and at-line sensors you want, but successful secondary pharmaceutical manufacturing still relies on people, carrying out simple tasks, repetitively and correctly, in a clean, safe hygienic environment, and writing down what they have done (either on paper, or using a keyboard). Get the right people, train them and supervise them correctly, and the warning letters will disappear. Contamination
operating range. At least five weights should be chosen, including a lower and upper range. Apart from this, balance verification should be performed for the full range specified by the supplier/manufacturer at least once a month. Note that while the inbuilt calibration shows that your system is satisfactory, auditors prefer to do external verification to prove the accuracy.
Response 2 – The daily check you are carrying out
– is just that. Your scale still requires to be included in a calibration schedule and calibrated in a manner traceable to national standards.
Steam steriliser validation
What pressure should be set for vacuum Q leak rate tests in steam sterilisers? The HTM 2010 guideline recommends 70mbar Abs pressure but what is the normal industry practice? How are regulatory inspectors taking the matter and what are their expectations?
After producing many batches of an oral Q dosage form, a very small insect inside one of the API containers was found in the
Response 1 – Previously we used a pressure of
manufacturing area. Quantities from the same API batch number were used in different finished product batches. We then performed biological testing for all the finished products but the results were negative. So is there any suggestion/ comments regarding our action? Is there any additional action we should take? Can we ship the produced batches based on the test results?
Response 2 – Leak tests are normally not
Response 1 – You should certainly not ship the
material even if it is proved to be free from any other material. This is exactly what is not allowed – you cannot test quality into a product.
Response 2 – I would go further and state that the
product should be rejected – the only sensible Corrective Action. Consider a customer complaint: “There is part of an insect in my tablet”. It is essential to audit the supplier and make your own assessment of the risk of more batches being contaminated. Ideally you will have had the insect identified – at least flying or crawling – which will help with the risk assessment.
Calibration vs verification
Q
We have a checkweigher for final product weighing ranging from 10gm to 500g. This checkweigher is calibrated by a 1,000g weight every day, through an inbuilt calibration system. Could anyone let me know whether verification with different weights is required or not?
Response 1 – First you should define the operating range in your SOP. After that, daily verification of the balance shall be performed by weights covering the
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70mbar for chambers but now we use 60mbar. What matters here is that the test establishes that the steriliser chamber does not leak either under vacuum or pressure.
performed on a hot autoclave. (Pressure being inversely proportional to temperature, change in temperature during the test will make it difficult to make sense of the values you get in a hot autoclave which is cooling during the test). The logic of using 60mbar in place of 70mbar is because there may be a slight rise in pressure during the stabilisation phase. The value is a guideline. You can establish your test and monitor trends of behaviour on your autoclave. The change in ‘trend’ of the value of the leak rate is what you are looking for. The reason why the guideline specifies an upper limit and lower limit for volume is because pressure is directly proportional to volume, the 1mbar/min leak rate is the limit within the volume band 200–600L. Outside this volume limit one has to factor volume to calculate leak rates. Imagine a scenario where you have a 1Litre/min leak in a 1,000L vessel at 100mbar abs and a 1Litre/min leak in a 500L vessel at 100mbar abs. The change of pressure in the 1,000L vessel will be much less than it is in the 500L vessel. Use this logic to work out your own values for your autoclaves.
Readers are invited to send their Q&As to www.pharmweb.net/gmp.html
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DATES FOR YOUR DIARY
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22-25 March 2010 – Stuttgart, Germany MEDTEC Europe www.cancom.com
A P R IL 12-13 April 2010 – Manchester, UK How to simplify and improve your deviation and CAPA system www.DBA-global.com 13-14 April 2010 – Munich, Germany Cleaning validation in biotechnology www.apv-mainz.de 19-20 April 2010 – Manchester, UK How to simplify and improve your batch record review process www.DBA-global.com 21-22 April 2010 – Koblenz, Germany Product and site transfers www.apv-mainz.de 26-28 April 2010 – Würzburg (nr Frankfurt), Germany Strategies against counterfeit medicines www.counterfeit-conference.org 27-28 April 2010 – London, UK Pharma IQ’s successful eCTD lifecycle management www.ectdevent.com 27-28 April 2010 – Birmingham, UK MEDTEC UK www.medtecuk.co.uk
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eur opean INDUSTRIAL PHARMACY • Issue 5 February 2010