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`3008331.436
`
`CELGENE 2145
`edited by
`APOTEX v. CELGENE
`IPR2023-00512
`E R Evans I H Hall
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`

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`

`

`PHARMACEUTICAL PACKAGING
`PHARMACEUTICAL PACKAGING
`TECHNOLOGY
`TECHNOLOGY
`
`

`

`New and Forthcoming Titles 1n the Pharmaceutical Sciences
`
`Nuclear Medicine in Pharmaceutical Research, Perkins & Frier (Eds) 1999, 0 7484 0688 3 (Hbk)
`
`Electrically Assisted Transdermal and Topical Drug Delivery, Ajay K. Banga 1998, 0 7484 0687 5
`(Hbk)
`
`Physiological Pharmaceutics Barriers to Drug Absorption (2nd Edition), Washington & Wilson
`1999, 0 7484 0562 3 (Hbk), 0 7484 0610 7 (Pbk)
`
`Microbial Quality Assurance in Cosmetics, Toiletries and Non-Sterile Pharmaceuticals (2nd
`Edition), Baird with Bloomfield (Eds) 1996, 0 7484 90437 6 (Hbk)
`
`Immunoassay A Practical Guide, Law (Ed.) 1996, 0 7484 0560 7 (Hbk)
`
`Cytochromes P450 Structure, Function and Mechanism, Lewis 1996, 0 7484 0443 0 (Hbk)
`
`Autonomic Pharmacology, Broadley 1996, 0 7484 0556 9 (Hbk)
`
`Pharmaceutical Experimental Design and Interpretation (2nd Edition), Armstrong & James
`1996, 0 7484 0436 8 (Hbk)
`
`Pharmaceutical Production Facilities (2nd Edition), Cole 1998, 0 7484 0438 4 (Hbk)
`
`Pharmaceutical Aspects of Oligonucleotides, Couvreur & Malvy (Eds) 2000, 0 7484 0841 X
`(Hbk)
`
`Pharmaceutical Formulation Development of Peptides and Proteins, Frokjaer & Hovgaard (Eds)
`2000, 0 7484 0745 6 (Hbk)
`
`Handbook of Microbiological Quality Control in Pharmaceuticals and Medical Devices,.
`Denyer, Baird & Hodges 2000, 0 7484 0614 X (Hbk)
`
`full pharmaceutical science catalogue available
`or visit our website on: http:/ /www.tandf.co._uk
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`

`

`PHARMACEUTICAL
`PACl(AGING TECHNOLOGY
`
`Edited by
`
`D. A. Dean
`Packaging Consultancy~ Education and Training~ Nottingham~ UK
`
`E. R. Evans
`Pharmaceutical Quality Assurance Consultant~ Wiltshire~ UK
`
`I. H. Hall
`Packaging Consultant for Pharmaceuticals and Security~
`Buckinghamshire~ UK
`
`London and New York
`
`

`

`First published 2000 by Taylor & Francis
`11 New Fetter Lane, London EC4P 4EE
`
`Simultaneously published in the USA and Canada by Taylor & Francis,
`29 West 35th Street, New York, NY 10001
`Taylor & Francis is an imprint of the Taylor & Francis Group
`
`© 2000 Taylor & Francis
`
`Typeset in Sabon by J&L Composition Ltd, Filey; North Yorkshire
`Printed and bound in Great Britain by
`T J International Ltd, Padstow, Cornwall
`All rights reserved. No part of this book may be reprinted or reproduced or
`utilised in any form or by any electronic, mechanical, or other means, now
`known or hereafter invented, including photocopying and recording, or in
`any information storage or retrieval system, without permission in writing
`from the publishers.
`
`Every effort has been made to ensure that the advice and information in this
`book is true and accurate at the time of going to press. However, neither the
`publisher nor the authors can accept any legal responsibility or liability for
`any errors or omissions that may be made. In the case of drug
`administration, any medical procedure or the use of technical equipment
`mentioned within this book, you are strongly advised to consult the
`manufacturer's guidelines.
`
`British Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutical packaging technology/ edited by D.A. Dean, R. Evans, I. Hall.
`p.; cm.
`Includes bibliographical references and index.
`ISBN 0-7484-0440-6 (hardback)
`1. Drugs - Packaging. I. Dean, D. A. (Dixie A.), 1923- II. Evans, R. (Roy) IIL Hall, I. (Ian)
`[DNLM: 1. Drug Packaging. 2. Technology, Pharmaceutical. QV 825 P536 2000)
`RS159.5 .P495 2000
`615'.18--dc21
`99-051910
`
`

`

`CONTENTS
`
`Contributors
`Preface
`Technical editor's note
`
`1
`
`An introduction to pharmaceutical packaging
`D. A. DEAN
`
`2 The packaging function: management, development and product
`shelf life
`D.A.DEAN
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Regulatory aspects of pharmaceutical packaging
`]. GLASBY
`
`Specifications and quality
`E. R. EVANS
`
`Paper- and board-based packaging materials and their use in pack
`security systems
`I. H. HALL
`
`Glass containers
`D. A. DEAN
`
`Plastics - an introduction
`D.A.DEAN
`
`Development and approval of a plastic pack
`D. A. DEAN
`
`Films, foils and laminations (combination materials)
`D. A. DEAN
`
`V
`
`vu
`IX
`
`X
`
`1
`
`34
`
`73
`
`104
`
`152
`
`210
`
`264
`
`326
`
`367
`
`

`

`CONTENTS
`
`10 Metal containers
`P. L. CORBY AND D. A. DEAN
`
`11 Closures and closure systems
`D. A. DEAN
`
`12 Sterile products and the role of rubber components
`N. FRAMPTON AND D. A. DEAN
`
`13 Blister, strip and sachet packaging
`D. A. DEAN
`
`14 The packaging line
`I. H. HALL
`
`15 Warehousing, handling and distribution
`l. H. HALL
`
`16 Printing and decoration
`D. A. DEAN
`
`17 Present and future trends
`D.A.DEAN
`
`Index
`
`404
`
`443
`
`492
`
`517
`
`547
`
`563
`
`582
`
`614
`
`625
`
`Vl
`
`

`

`CONTRIBUTORS
`
`P. L. Corby
`(BA, F.Inst.Pkg.)
`Retired
`
`D. A. Dean
`(B.Pharm., F.R.Pharm.S., FSS, DBA, F.Inst.Pkg., FIP, SA)
`Consultant
`Dixie Dean Packaging Consultancy
`Education and Training
`
`E. R. Evans
`(F.Inst.Pkg., MIQA)
`Consultant
`Pharmaceutical Qu;:llity Assurance
`
`Dr N. Frampton
`(Ph.D., C.Chem., MRSC)
`Business Development Manager
`Ernest Jackson Ltd
`Dr J. Glasby
`(Ph.D., B.Pharm., BA (Law), M.R.Pharm.S.)
`Managing Director
`Kendle International Ltd
`
`I. H. Hall
`(BA, M.I.Mgt., M.Inst.Pkg.)
`Consultant
`Packaging Consultants for Pharmaceuticals and Security
`
`Vll
`
`

`

`3
`
`REGULATORY ASPECTS OF
`PHARMACEUTICAL PACKAGING
`
`]. Glasby
`
`Introduction
`
`The pharmaceutical industry· is one of the most highly regulated industries in the
`world, the aerospace industry perhaps being the only one more highly regulated.
`Control is imposed on:
`
`1
`
`2
`3
`
`4
`
`5
`6
`
`how the product is developed (toxicology testing is controlled through good labo(cid:173)
`ratory practice (GLP); clinical testing is controlled by good clinical practice (GCP))
`how the product is manufactured (through good manufacturing practice (GMP))
`how the product is sold (through controls imposed through the Product Licence
`Application (PLA))
`how the product is labelled (in Europe through the Labelling Directive and sum-
`mary of product characteristics (SPC))
`how the product is advertised (in Europe through the Advertising Directive)
`how the product is disposed of (in Europe by the ·Packaging Waste Directive).
`
`Thus, from the origination of the first idea to the final sale of the product, the legal sys(cid:173)
`tem plays a key role in shaping and controlling the product. In this chapter we are par(cid:173)
`ticularly interested in how regulatory demands affect packaging.
`
`Definition of the pack
`
`The packaging technologist defines the pack as 'a device for carrying and protecting the
`product from producer to user', thus it is involved in containment, convenience, compli(cid:173)
`ance, and confidence. The regulator, however, is interested in only some of these aspects
`(Table 3.1). In particular, the regulator sees the pack as having the following characteristics:
`
`1
`
`containing the product
`
`•
`•
`•
`
`protection of the product
`protection of the consumer
`dosage control
`
`2
`
`carrying the label
`
`•
`•
`
`legal control of the product
`informing the recipient
`
`73
`
`

`

`]. GLASBY
`
`Table 3.1 Respective areas of interest of pack definition
`technologist and regulator
`
`Area of interest
`
`Technologist
`
`Regulator
`
`X
`X
`X
`
`X
`X
`X
`
`Economics
`Protection
`Identification
`Contain1nent
`Convenience
`Market appeal
`Presentation
`Disposal
`Compliance
`Primary pack
`Secondary pack
`Tertiary pack
`
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`
`3
`
`contaminating the environment
`
`•
`•
`
`packaging waste
`ozone depletion
`
`4
`
`protecting the consumer
`
`•
`•
`
`child-resistant closures
`tarn.per-evidence.
`
`The pack as a container of the product
`
`At one time the container excited little interest since, it being invariably made of glass,
`there was little potential interaction with the product. The glass bottle was regarded as
`little more than an inert receptacle. Since there were also severe limitations on the form
`of the glass bottle there was little scope for ingenuity, thus packaging development
`tended to be considered as a separate topic tagged onto the end of the development
`programme, i.e. almost as an afterthought. Now the situation is different, and product
`development is totally integrated with packaging development. Of course, the packag(cid:173)
`ing technologist had been saying for years that packaging development cannot be sepa(cid:173)
`rated from product development, insisting that it was not possible to separate the pack
`and product. Why then has the attitude of industry and the regulators changed? There
`are several factors, as detailed below.
`
`Increasing sophistication of the pack
`
`Glass, being so inert, does not present a very interesting problem to the packaging tech(cid:173)
`nologist. Once plastics are involved, however, the situation changes and there is much
`more scope for interactions between product and packaging. Packs can also be
`designed to be more closely tailored to the needs of the patient. Like all advantages,
`however, there are associated disadvantages to the use of plastics, for example the
`extraction of materials from the plastics into the product. Once the possibility of con(cid:173)
`tamination arises, regulatory authorities become much more interested in the selection,
`composition and performance of the package.
`
`74
`
`

`

`REGULATORY ASPECTS
`
`Increasing sophistication of the product
`
`New chemical entities are so few and far between these days, and are so expensive to
`develop that companies regularly look at their ageing products with a view to revamp(cid:173)
`ing them by means of new presentations. One way to do this is to repackage the prod(cid:173)
`uct in a more sophisticated way. Once there is more complexity, there is greater
`potential for problems to occur between the pack and product.
`
`Incorporating a device into the pack
`
`Control of dosage and administration has always been interesting both to pharmacists
`and to regulators, but it can be a major problem with pharmaceutical products. The
`pack can play a key part in controlling the dosage, for example in the use of a pres(cid:173)
`surised aerosol for dispensing powders or solutions. Once the pack and product admin(cid:173)
`istration system are integrated in this way the development cannot be separated and
`neither can they be separated in regulatory terms. A drug is thus affected by its pack(cid:173)
`aging, both in practice and in the eye of the regulatory authority. For example, in the
`USA a parenteral drug product, even if it is an old drug such as sodium chloride, when
`produced in a plastic container does not fall within the category of 'generally recog(cid:173)
`nised as safe' (GRAS). It is regarded as a new drug (Federal Food, Drug and Cosmetic
`Act S201 (P)).
`
`Cost of development
`
`It is not only the development of new chemical entities that is becoming more and more
`time-consuming and, thus, expensive (Table 3.2). The cost of development of any prod(cid:173)
`uct is now so high that a company must look to worldwide distribution in order to
`recoup the development costs. Ideally the same product should be used worldwide.
`However, while the pharmaceutical development department will be trying to develop
`a single formulation, the pac;:kaging development department's aim must also be to try
`and develop one single pack for worldwide use. This trend, however, will be countered
`by marketing departments trying to obtain precisely the right presentation for each
`market, insisting that markets differ in their needs.
`Just as market needs differ, local regulatory agencies also have different require(cid:173)
`ments. While it may be possible to convince marketing departments at least to reduce
`the number of variants required, what about all the different regulatory agencies, of
`
`Table 3.2 Time to develop new
`drug
`
`Activity
`
`Research
`Toxicology
`Development
`Clinical
`Registration
`Total
`
`Time
`(years)
`
`2
`3
`3
`4
`?
`12+
`
`75
`
`

`

`J. GLASBY
`
`which there are over 150 in the world? How can they be satisfi~d by the same product
`and data?
`In regulatory terms the situation is not quite as bad as it might appear. If we look at
`the world market (Figure 3.1), the EU represents approximately 30% of the market, the
`US approximately 27% and Japan approximately 18% . In total this represents 75% of
`the total market. Therefore, in commercial terms if one can satisfy these countries then
`a large step has been made towards meeting the commercial goal.
`the International Conference on
`This situation has been improved through
`Harmonisation (ICH) between these three areas, since agreement has been reached on
`stability testing, impurities of active materials and others. As this expands, the multi(cid:173)
`plicity of data requirements will be significantly reduced. However, although there is
`some harmonisation between the three major regulatory areas in terms of the data
`required, it is likely that in regulatory terms the world will continue to be split into
`three different types of regulatory system: EU, USA and Japanese. Other countries will
`tend to follow one of these approaches with local modifications.
`
`Regulatory authorities - background
`
`The EU, although under criticism in many areas, has been fairly successful in the phar(cid:173)
`maceutical area, with the following achievements:
`
`•
`•
`•
`•
`•
`
`centralised system in place
`decentralised system in place
`harmonisation of format
`expanding acceptance of format outside EU
`harmonisation of standards (PH EUR).
`
`A standard format of product licence application has been adopted, making the prepa(cid:173)
`ration of regulatory documents much simpler. The format and data requirements of
`
`■ USA
`■ Europe
`m Japan
`II Rest
`
`Figure 3.1 The world pharmaceutical market
`
`76
`
`

`

`REGULATORY ASPECTS
`
`the EU are being adopted by several countries outside the union, so reducing the num(cid:173)
`ber of types of application necessary.
`The Food and Drug Administration (FDA) is finally recognising the competence of
`certain overseas agencies and the skill of scientists, and accepting more data that has
`been generated overseas (Figure 3.2). Even Japan is becoming more international, with
`several initiatives suggesting, in theory at least, that data from overseas should be
`acceptable within Japan.
`· In order to understand the approach of regulatory authorities, it is necessary to
`understand their attitudes and for this it is necessary to look back into history.
`The history of pharmaceutical products is, in fact, rather short (Figure 3.3). Before
`the nineteenth century there were few really effective drugs apart from a few herbal
`remedies such as digitalis from foxglove. In general, only herbs and spices were used in
`treating disease. Since they had variable and unproven efficacy, the main perceived
`problem was that herbs and spices were expensive. Certain unscrupulous dealers
`tended to dilute the material in order to maximise profit, and this led to the introduc(cid:173)
`tion of the first control o( drugs. First local pharmacopoeias and then country-wide
`pharmacopoeias were introduced which defined the specific composition and quality to
`be applied to drugs.
`In the nineteenth and early twentieth century, with the increased urbanisation and
`industrialisation of the UK, the majority of medicines were the so-called patent medi(cid:173)
`cines which contained few active ingredients but had extensive claims for their curative
`actions. Thus, the controls that had to be applied were on the advertising and claims
`for the product. It was only after 1935 that the 'therapeutic revolution' brought prod(cid:173)
`ucts which actually had some proven and consistent efficacy. Unfortunately, along with
`the efficacy came side-effects and problems, since for every pharmacological activity
`which is beneficial there will inevitably also be side-effects. If we look back at the intro(cid:173)
`duction of controls on medicines, it is generally a problem or disaster which leads to
`introduction of the specific control.
`In the USA, the death of a large number of children from a sulphanilamide prepara(cid:173)
`tion led to the Food, Drug and Cosmetic Act (1938). For the first time, proof of safety
`was required before any product was introduced to the market. It was not until the
`1962 thalidomide tragedy that proof of efficacy was required in the USA through
`an amendment to the FD&C Act, the Kefauver Amendment, and this led to the
`
`EU expanding
`
`FDA recognising competency of overseas
`
`""
`
`~C i~
`
`JAPAN becoming more international
`
`~~~
`
`International Conference on Harmonisation (ICH)
`
`Figure 3.2 The worldwide regulatory split
`
`77
`
`

`

`Pre-19th century -
`
`i
`i
`
`19-20th century -
`
`1935 onwards -
`
`J. GLASBY
`
`herbs/spices - - - - - adulteration - - pharmacopoeias
`
`patent medicine -
`
`wild claims
`
`- - - advertising
`labelling controls
`
`therapeutic revolution
`
`~
`
`efficacy _____ _.,... adverse effects
`
`........ legal controls
`
`(NDNPLA) ~ t
`
`sulphanilamide 1937 - - - - - - - - - - FD&C Act 1938
`
`~
`
`thalidomide 1962 - - - - - - - - - - Kefauver Harris Amendment
`Medicines Act 1968
`
`Figure 3.3 Outline of pharmaceutical history
`
`introduction of other regulatory controls worldwide including the Medicines Act 1968
`in the UK. Such problems, together with other factors such as political pressure, public
`pressure, consumerism and bureaucracy, have created the regulatory agency attitudes
`we see today.
`Despite the differences in regulatory agencies, the actual registration approach is
`very similar (Figure 3.4). The process starts with the research area producing com(cid:173)
`pounds for evaluation, followed by toxicology testing, first in animals and then the first
`introduction into human volunteers to determine safety and tolerance. This is followed
`by small clinical efficacy studies and finally the Phase III full efficacy studies involving
`large numbers of patients. In parallel to these clinical programmes the product devel(cid:173)
`opment progresses with finalisation of the formulation and pack, and stability testing.
`Once sufficient clinical and pharmaceutical data are available, the product licence
`application can be prepared and submitted to the authorities. For review, it is generally
`
`Pharmaceutical development
`
`Development stability
`
`Formal stability
`
`Animal testing
`evaluation
`
`1
`
`IND
`CTX
`
`Phase I
`
`Phase II
`
`·Phase III
`
`Dossier
`
`1
`
`NDA
`PLA
`
`Figure 3.4 The development process
`
`78
`
`

`

`REGULATORY ASPECTS
`
`split into the three different sections, chemistry and pharmacy, pre-clinical studies and
`clinical data, so that the:'e separate parts can be examined by specialist reviewers. It is
`almost certain that reviewers will have questions during their review which have to be
`circulated back to the company while the application is put on hold, pending suitable
`replies. This circuit may be followed several times and, in part, explains why the review
`cycle can be so long and variable. Finally, once all the questions have been resolved and
`the precise labelling agreed, a licence is issued and the product can be launched.
`
`European Union processes for drug evaluation
`
`Within the EU there are currently three processes by which a drug can be approved for
`marketing (Table 3.3). These are individual local applications to specific countries, the
`decentralised system, (mutual recognition route), and the centralised system.
`
`Local applications
`
`For products intended for a single country a local application can be made. Since 1
`January 1998 any subsequent application to a second country must be made through
`the decentralised system.
`
`Decentralisedsystem (mutual recognition)
`
`1:·he decentralised system is, in effect, a system of mutual recognition. An application is
`first made in a single country and when approved the application, translated in certain
`aspects, along with the assessment report prepared by the regulatory agency, is sent to
`the other countries. Each country then has a limited time to accept the application and
`assessment report or to provide reasoned objections. If the objections cannot be
`resolved by bilateral discussion then the application is referred to the CPMP for a bind(cid:173)
`ing recommendation (Figure 3.5). Alternatively, the country or countries with objec(cid:173)
`tions can be withdrawn from the procedure. Although not without its problems, the
`system is working and products are receiving approvals in many European countries by
`this route. At present however, individual countries tend to be carrying out a full review
`of the applications despite the availability of the original approval and assessment
`report, and have not yet fully embraced the idea of mutual recognition.
`
`It was recognised that certain products, such as biotechnology products, were taking a
`considerable period to become registered in Europe because of their complexity and
`
`Centralised system
`
`Table 3.3 EU processes
`
`Local applications
`
`Decentralised applications
`
`Centralised applications
`
`After 1998 for one country only
`
`Mutual recognition
`Majority of applications
`Innovative products and biotechnology
`Single licence for all EU
`
`79
`
`

`

`J. GLASBY
`
`Application to first member state
`
`210 days
`
`l
`First Troval ~
`
`Assessment report
`
`Updated
`application
`
`90 days
`Application for mutual recognition
`
`~ l
`
`No objections
`
`60 days
`
`Bilateral phase
`
`CPMP arbitration
`
`National decision
`
`CPMP opinion
`
`Serious objections
`
`Serious objections
`30 days
`
`90 days
`
`60 days
`
`l
`l
`i
`i
`i
`
`Company appeal if negative
`
`Final opinion
`
`Commission decision
`
`Figure 3.5 The mutual recognition process
`
`the absence of skills to evaluate them in certain countries. A central scheme was there(cid:173)
`fore set up where by a single evaluation of the application is made and a recommenda(cid:173)
`tion for approval issued by the CPMP followed by issue of a single licence issued by the
`London-based European Medicines Evaluation Agency (EMEA) for all the EU (Figure
`3.6). Since 1 January 1995 this centralised procedure has been mandatory for all prod(cid:173)
`ucts of biotechnology and optional for projects which a~e very innovative such as new
`chemical entities or new presentations of drugs. CPMP appoints one or two of its
`members to act as rapporteur to co-ordinate the assessment using the facilities of the
`various regulatory agencies within Europe. Once the evaluati0n reports are available
`the CPMP makes an opinion within 210 days of receipt of the application and a single
`licence is then granted, valid throughout the Union.
`
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`

`REGULATORY ASPECTS
`
`Submission of dossier and
`start of procedure (review)
`
`Receipt of assessment reports from
`rapporteurs by CPMP and EMEA
`
`Receipt of questions and conclusion from
`rapporteurs, validation
`
`Receipt of questions by applicants
`
`Submission of response
`
`Common response assessment report to
`CPMP and EMEA
`
`1 70 days
`j 30 days
`CPMP comments l 20 days
`j
`j clock stops
`l 30 days
`j 20 days
`j 15 days
`j
`j
`j
`
`Deadline for CPMP comments
`
`Oral explanation ------------J►
`from company
`if needed
`(day 210)
`
`Submission of final draft of SPC (English)
`
`CPMP opinion and draft assessment report
`
`Submission and labelling translation, pack mock-ups
`
`Finalisation of CPMP assessment report
`Opinion to applicant
`
`Figure 3.6 Outline of the centralised procedure
`
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`

`J. GLASBY
`
`Product licence applications - data requirements on the package
`
`A few years ago there was almost no legislation concerning packaging. The 1968
`Medicines Act in the UK, for example, makes almost no mention of the subject.
`However, for the reasons discussed earlier, certain specific EU guidelines applying to
`packaging have now been published. These are:
`
`•
`CPMP List of Allowed Terms (III/3593/91) (new list issued in February 1998)
`• Notice to Applicants (Updated 1998)
`•
`Plastic Container Guidelines (III/9090)
`•
`Plastics in Contact with Food Directive (90/128).
`
`These, along with the requirements of the European Pharmacopoeia, provide guidance
`for the data requirements for packaging and its format for presentation in the product
`licence application.
`
`CPMP list of allowed terms
`
`Descriptive terms for pharmaceutical forms, routes of administration, and packaging
`and delivery systems allowed to be used in a Product Licence Application are now pre(cid:173)
`scribed by EU Regulations (Table 3.4). It is hard to understand the value of this legisla(cid:173)
`tion except in terms of the legal nature of the Product Licence Application. It must be
`remembered that a product licence is more a legal than a truly technical document. As
`with all legal documents, it is necessary to ensure the definitions are consistent wher(cid:173)
`ever the application is made. It is not clear, however, how much attention is being given
`by regulatory agencies to this list, although experience has suggested that they do insist
`on using the appropriate terms in at least the application form part of the submission,
`since this becomes the legal body of the licence. The official terms should also be used
`in the labelling, particularly the summary of product characteristics.
`
`Notice to applicants
`
`The main pharmaceutical Directives 65/65 and 75/318 do not actually spell out in
`detail what is required in a Product Licence Application. These key directives require
`that applications be made, and define only in outline the data requirements. It is
`therefore necessary to expand the guidance and this is done in the Notice to
`Applicants (1986) and its subsequent amendments. The Notice to Applicants pre(cid:173)
`pared by the European Commission has no legal standing, but gives additional advice
`over and above that given in the various EU Directives. The notice actually forms vol(cid:173)
`ume 2 of 9 volumes of the Rules Governing Medicinal Products in the European
`Union, and has two parts:
`
`•
`•
`
`2A deals with the legal procedures for marketing authorisation
`2B deals with the presentation and content of the application dossier.
`
`In these documents the Marketing Authorisation Application is defined in the follow(cid:173)
`ing sections.
`
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`

`REGULATORY ASPECTS
`
`Table 3.4 Standard terms for marketing authorisation applications, Notes for Guidance III
`3593/91 EN :final (updated February 1998)
`
`Covers standard terms for:
`pharmaceutical dosage forms
`•
`route of administration
`•
`container
`•
`closure
`•
`administration device.
`•
`
`Containers
`Ampoules
`Applicator
`Automatic injection device
`Bag
`Balling gun
`Barrel
`Blister
`Bottle
`Box
`Brush
`Brush applicator
`Cannula
`Cap
`Cartridge
`Child-resistant closure
`Cup
`Dabbing applicator
`Dart
`Dredging applicator
`Dredging container
`
`Drench gun
`Dropper applicator
`Gas cylinder
`High pressure transdermal
`delivery device
`Implanter
`Inobo injection device
`Injection needle
`Injection syringe
`Internal graduated calibration
`chamber
`lntramammary syringe
`Jar
`Measuring spoon
`Metering pump
`Metering valve
`Mouth piece
`Nasal applicator
`Nebuliser
`Needle applicator
`Nozzle
`
`Oral syringe
`Pipette
`Pour-on container
`Pre-filled syringe
`Pressurised container
`Sachet
`Scarifier
`Screwcap
`Single dose container
`Spatula
`Spot-on applicator
`Spray container
`Spray pump
`Spray valve
`Stab vaccinator
`Stopper
`Strip tablet container
`Tube
`Vaginal sponge applicator
`Vial
`
`•
`
`Section I:
`
`application form, administrative details, labelling and expert reports
`(chemistry and pharmacy, toxico-pharmacological, and clinical).
`chemistry and pharmacy data.
`Section II:
`toxicology data.
`Section III:
`Section IV: clinical data.
`
`•
`•
`•
`For most of our purposes, the ,data on packaging is included only in the chemistry and
`pharmacy section and in the pharmaceutical expert report, although if a new plastic or
`polymer material is used, toxicology data may be required along with cornment in the
`toxicology expert report.
`With Section II, data is required on the packaging in four areas:
`
`•
`•
`•
`•
`
`Section IIA2:
`Section IIA4:
`Section IIC3:
`Section 11F2:
`
`immediate package
`compos1t10n
`development pharmaceutics
`control of starting materials
`stability testing.
`
`The Notice to Applicants remained the only guidelines available until 1990, when the
`draft Plastic Container Guidelines III/9090 was published which expanded the require(cid:173)
`ments in these four areas (Table 3.5).
`
`83
`
`

`

`J. GLASBY
`
`Table 3.5 CPMP Guideline III/9090 EN final, plastic primary packaging materials
`
`Take account of:
`Directive 90/128/EEC - plastic materials intended to come into contact with foodstuffs
`•
`European Pharmacopoeia
`•
`Notice to applicants
`•
`Volume IV of Rules Governing Medicinal Products in European Community. Parts
`•
`covering packaging:
`- IIA2 immediate packaging
`- IIA4 development pharmaceutics
`- IIC3 packaging materials
`- IIF2 stabilit .
`
`MAA application section IIA2 - container
`
`This requires only a brief description of the nature of the container and of the compo(cid:173)
`nents, with a qualitative composition and details of the method of closure and opening
`(Table 3.6).
`
`MAA application section IIA4 - development pharmaceutics
`
`The development pharmaceutics area is often neglected, but is proving to be a key area
`in submissions. In this section the applicant must justify the choice of the formulation
`and of the packaging. Thus, the selection of the resin must be discussed and data pro(cid:173)
`vided on the interaction or compatibility between product and pack. If there is pro(cid:173)
`cessing involved, such as sterilisation, then the influence of the process on the product
`and container must be studied and reported (Table 3.6).
`
`MAA application section IIC3 - control of starting materials
`
`The container is regarded as one of the starting materials for the product along with
`the other ingredients of the formulation. For this reason the specification, testing regi(cid:173)
`men and details of any tests carried out must be provided for both the plastic resin
`material and the container (Table 3.7).
`
`Resin
`
`The name of the resin material, the name and address of the manufacturer, the chemi(cid:173)
`cal name, the complete formulation, characteristics and quantity of all ingredients and
`the function are required where the material is to be used in a container which will be
`exposed very intimately to the product, such as a large volume parenteral solution or
`eye drop. The identity, using IR absorption along with a reference spectrum must be
`provided. Additives, particularly those likely to migrate, including antioxidants, plasti(cid:173)
`cisers, catalysts, initiators and materials such as phthalates, adipates and organic tin in
`PVC or any dyes used in the resin must also be identified.
`Tests on plastics should include physical, mechanical, dimensional, purity in terms
`of monomer and additives, buffer potential, reducing substances and UV absorption.
`If the material is not listed in the European Pharmacopoeia then its status as a food(cid:173)
`approved plastic must be described with reference to the EU Directive. If these data are
`
`84
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`

`

`REGULATORY ASPECTS
`
`Table 3.6 CPMP Guidelines III 9090
`
`IIA2 Immediate packaging
`Description container including:
`nature o