As the pharmaceutical industry prepares to

meet the challenges of the new millennium,

there is a distinct sense of optimism among

drug delivery technologists that the industry is

set to see significant advances in the capabil-

ities of drug delivery systems (DDS). At a recent

IIR conference, Maximising Value & ExtendingProduct Life Through Effective Drug DeliverySystems (29–30 March 1999, London, UK), dis-

cussion was largely focused on analysis of the

strengths of existing technologies and their im-

plementation, and yet, interestingly, this was

stretched to discuss at length the next gen-

eration of delivery systems.

Day one of the conference, chaired by Andrew

Edwards (Core Technologies Ltd, Irvine, UK),

opened with a keynote presentation by Harry

Ferres (SmithKline Beecham Pharmaceuticals,

Harlow, UK), in which he reviewed 20th century

DDS progress and offered an outline of his vision

for future industry developments in this area.

Ferres began by providing a clear definition

of the role of the DDS; that is, to deliver the

drug to the correct place, at the correct time

and in the correct amount. He stated that cur-

rently more than 90% of DDS are tablets, and

that it is likely that although this dosage form

will undergo fundamental changes in design,

manufacture and performance, it will continue

to hold its position as the long-term dosage

form of choice. This was followed by an analysis

of the level of progress that has hitherto been

achieved in this area. According to Ferres, cur-

rent progress has significantly failed to reach

expected levels, and he claimed that in terms of

the achievement of the objectives of drug deliv-

ery, it is probable that developments in this

century, on a scale of 1–10, will receive a poor

rating of no more than two or three.

Century gapBased on this disappointing figure, Ferres urged

technologists to work towards what he identi-

fied as a gap to be filled in the next century,

moving DDS from beyond modified release

(MR) and on to more complex release profiles

that are compatible with pathophysiological

considerations. According to Ferres, chrono-

pharmacological release should become the pri-

mary target in such efforts, and research into

topics such as the identification of novel cellu-

lar transporters in both normal and diseased

states is required so that new targeting strat-

egies are made available and thus make drug

targeting a reality.

It would seem that increased performance is

the key to future progress in DDS. In short, the

industry needs to move from tablets produced

by using similar methods to the baking industry

(in which therapeutic efficacy is mainly inde-

pendent of the DDS), and move towards the

‘smart tablet’ of the 21st century, thus perhaps

spelling the end of broad usage of terms such

as ‘immediate release’ and ‘controlled release’. It

is hoped that the smart tablet will feature pro-

grammed release capable of offering maximum

pharmacokinetic/pharmacodynamic (PK/PD) ben-

efits in a manner that is in keeping with

pathophysiological consideration. Indeed, it is

expected that advances in tablet making

technologies will be introduced and that these

will allow polypharmacy in single tablet units,

thus leading to increased patient compliance.

Ferres believes that the likelihood of success in

these smart DDS will offer an incentive for

manufacturers to perform outcome benefit

studies, providing suitable justification for pre-

mium costs.

The key point of the presentation was that, in

the eyes of Ferres, we have hitherto seen only the

‘tip-of-the-iceberg’ in terms of realizing the value

of DDS, and thus it could be argued that the fu-

ture should offer lucrative benefits to both manu-

facturers and patients. Indeed, Ferres believes that

the future holds enormous promise subject to the

fact that constraints are identified and tackled, the

direction taken by DDS is aligned with future

medicines, and DDS strategies are adapted to suit

the changing healthcare environment. In addition,

Ferres also argues that there are numerous con-

straints that are hindering progress, and that

the area requires increased emphasis on a multi-

disciplinary approach, with more consideration

directed towards PK issues in drug design, and

more effort and commitment in this area from the

major companies that would go some way to

matching that of the niche organizations.

In conclusion, Ferres identifies a number of

changes that he claimed must be implemented

to achieve an improved environment for the

development of future DDS.

• A move from site-indifferent to site-specific

targeting. Ferres claims that the extent to

which this aim is achieved will determine

whether the objectives of drug delivery, as

outlined earlier, are met.

• A shift in emphasis from device-driven

dosage form designs based on in vitro prop-

erties to pathophysiological-driven DDS de-

sign to achieve high in vivo performance.

PSTT Vol. 2, No. 6 June 1999 update conferences

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00165-0 225

Drug delivery systems in the20th century: merely scratchingthe surfaceAdrian Smith, Pharmaceutical Science & Technology Today, tel: 144 1223 315961, fax: 144 1223 464430, e-mail: pstt@elsevier.co.uk

• A move towards an increasingly scientific,

hi-tech approach to DDS design and manu-

facture, facilitating greater control of prod-

uct quality and performance.

• Increased usage of medicines tailored to

meet individual therapeutic requirements.

• Increased emphasis on the development of

DDS that can contribute to the ultimate

value of a medicine, such as by optimization

of the PK/PD response.

• The DDS should become an integral feature

of any new medicine, rather than a feature

to be added later in the development

process.

In view of these requirements, Ferres claimed

that unless these changes are made, the full

potential of the contribution of DDS will fail to

be realized in the 21st century.

Product lifecycle managementCees Winnips (Skyepharma, London, UK) outlined

methods for the development of DDS through

the formation of joint ventures and collabora-

tions with pharmaceutical and biotechnology

drug delivery companies. Winnips emphasized

the changing environment of the pharmaceuti-

cal industry and its associated pressures of cost

containment, financial expectations, technologi-

cal and regulatory issues, and the difficulties as-

sociated with innovative science.

In response to these challenges, Winnips

identified lifecycle management as key to deal-

ing with issues such as new indications, formu-

lation challenges, non-drug components, pack-

aging, and the importance of developing a

strong business rationale in achieving the ideal

of low-risk development and maximum profit,

patent protection and sales maintenance.

Mike Dey (Rhône-Poulenc Rorer, Holmes

Chapel, UK) maintained the theme of the previ-

ous presentations in first supporting the value of

DDS and the importance of future development,

and he then took the issue towards patient ben-

efit with a discussion of the selection of a drug

delivery system that will maximize drug efficacy.

With this in mind, Dey also argued that invest-

ment in DDS technology must be protected by a

high degree of intellectual property through the

use of patent or exclusivity agreements, and that,

once protected, a major factor in the commercial

success of a product is to be found in the speed

with which a product may be brought to market.

In his conclusion, Dey suggested that those com-

panies that are to be successful in achieving

rapid market entry for their drug will be those

that have followed some key steps.

• More effective management of the interface

with external experts, with their inclusion in

the internal team and decision processes.

• Vigorous employment of objective and

structured decision tools.

• Management based around a detailed and

updated specification that controls both

performance and cost.

• Regular critical reviews of progress to this

specification and project timelines will have

been performed.

• A programme of clinical and laboratory

testing that proves the development of sys-

tem functionality.

Meeting regulatory requirementsBased on these predictions of significant devel-

opments in new DDS, David R. Jones (Medicines

Control Agency, London, UK) provided an out-

line of the major short- and long-term regu-

latory requirements and issues to be faced by

manufacturers. These included methods for ac-

cessing data relating to additives and excipients

incorporated into licensed products, and clarifi-

cation of both bioequivalence and bioavailabil-

ity issues and the regulatory requirement for

safety data on additives and excipients.

Jones suggested that the best way to keep

updated with the latest regulatory requirements

is to subscribe to MAIL, the MCA Updating

Service, and the MCA EuroDirect Publication

Service. MAIL offers general guidance to manu-

facturers and lists all recent EuroDirect publi-

cations, and the MCA EuroDirect service

provides copies of all European Union and

International Conference on Harmonisation

guidelines and guidance notes.

Delegates were urged to contact the MCA

with their queries relating to regulatory issues,

and Jones emphasized that current – and poss-

ibly future – guidelines will remain ‘guidelines’,

and it is unlikely that they will even be able to

cope with the broad range of products that are

set to emerge just within the next ten years.

Day two of the conference, chaired by

Paulette E. Setler, began with a discussion of en-

hanced drug delivery technologies. Lisbeth Hume

(Schering-Plough Corporation, Kenilworth NJ,

USA) described the requirement for drug discov-

ery technologies and factors affecting drug de-

livery. Hume cited new issues and approaches,

the availability of new protein and peptide

drugs and economic factors as the driving

forces behind DDS development. Examples of

recent developments include oral controlled-

release formulations, buccal and transdermal

patches, liposomes and needlefree devices, and

yet Hume suggested that future development

may centre on new active substances, im-

proved therapy and maximized value through

line extensions. Furthermore, it was suggested

that future strategies should be directed to-

wards concentrating on directing resources to-

wards unmet delivery needs, the creation of a

delivery research centre and the selection of

drug delivery partners.

Hume offered an insight into what she sees

as future prospects for the industry, namely

once-daily medications, needleless protein

and peptide delivery, the application of gene

therapy (for some applications) and the recog-

nition of drug delivery initiatives as a critical

component of the pharmaceutical industry.

Drug delivery systems in IndiaOn a more specific level, H.L. Balla (Indian Local

Chapter of Controlled Release Society, Mumbai,

India) offered an excellent insight into the status

of DDS in India. Balla stated that although India is

the World’s tenth largest industrial nation, per

capita drug consumption remains very low, de-

spite low drug prices, and the potential of DDS

remains unexploited. In addition, the discovery

rate of new chemical entities is decreasing, and

the industry has limited resources with which to

invest in R&D for new drug discovery and devel-

opment. In view of this situation, the Indian phar-

maceutical industry is turning towards new DDS

which, according to Balla, offer low development

costs and opportunities for alliances (in both de-

velopment and marketing), and he cited modified

release products, liposomes, microemulsions,

update conferences PSTT Vol. 2, No. 6 June 1999

226

nasal, transdermal and transmucosal delivery sys-

tems, and implants as new DDS of potential mar-

ket value. Indeed, Balla concluded by suggesting

that, in the future, current drug delivery research

may provide an excellent business opportunity for

the Indian pharmaceutical industry.

Paulette Setler (Elan Corporation) brought

the conference to a conclusion with her ex-

amination of oral systems for the delivery of

peptides and proteins and poorly soluble mol-

ecules. She presented data from Elan

Pharmaceutical Technologies (EPT) demonstrat-

ing the delivery of pharmacologically signifi-

cant amounts of protein therapeutics encapsu-

lated in microparticles targeted to specific

receptors on the lumenal surface of intestinal

epithelial cells. Setler also drew on the technol-

ogies developed by the NanoSytems division of

EPT, which, through the nanonization of drug

crystals, is claimed to improve dissolution and

oral absorption, and also offer advantages in

pulmonary and parenteral drug administration.

These emerging technologies typify the vision

outlined by Ferres in the opening presentation,

in that, if managed correctly, DDS could emerge

as the key technological development of the

pharmaceutical industry in the next century.

PSTT Vol. 2, No. 6 June 1999 update books

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00159-5 227

International Stability Testing, edited by

David J. Mazzo, Interpharm Press, Inc., 1999.

(332 pages) ISBN: 1 57491 078 7

Stability testing can be complex, costly and

time-consuming and does not necessarily

guarantee that product characterized in formal

programmes will retain its quality during stor-

age and use. Indeed, laboratory tests can never

replicate precisely the diversity and complexity

of conditions in the field, and thus shelf-life

allocation can be a precarious undertaking.

The so-called ‘Guidelines’ that different

countries and economic trading groups have

historically applied to stability testing are

themselves, diverse. Although guidelines by

name, they tend to be viewed as requirements

in practice, and few applicants for product

licences choose to ignore them.

The numbers of stability tests has burgeoned

in recent times, reflecting the onward march of

guidelines, the globalization of the industry,

and the desire for companies to hurry new

medicines to the marketplace. As a result, clini-

cal programmes are often run in parallel rather

than sequentially. Hence, there is a need to test

a plethora of product strengths so that filings

can be expedited after the determination of the

safety, efficacy and dosing regimens. The emer-

gence of bracketing and matrixing is one

response to the need for an increase in the level

of testing.

There have been laudable attempts to har-

monize stability testing requirements under the

aegis of the International Conference on

Harmonisation (ICH). Primary guidelines have

now been agreed and put in place, with more to

come for secondary issues such as excipient and

process changes. David Mazzo’s InternationalStability Testing is largely devoted to what has

emanated from ICH and the implications for

testing programmes. The list of contributors is

truly transnational and includes representatives

from industry, regulatory agencies, learned in-

stitutions and contract organizations, and also

includes a contribution from the World Health

Organization. The text reads well and the narra-

tive style is consistent from chapter to chapter,

a praiseworthy achievement for a volume with

multiple and diverse contributors.

Specific topicsChapters are also devoted to topics such as

preservative efficacy testing, stress testing and

solid state stability. These vary in detail from

superficial reviews to a detailed treatise in the

case of preservative efficacy testing. Some pro-

vide good accounts of approaches and tech-

niques designed to characterize particular types

of behaviour, whereas others tend to be

generic. The chapter on solid state characteriz-

ation, for instance, lists many techniques but

does not give these much context, in terms of

determining the propensity for change in a

drug substance or dosage form.

Statements contained in more than one

chapter relating to studies to elucidate the ‘ki-

netics’ of degradation or degradation product

formation can also be considered naïve. The

complexities of solid state degradation rarely

allow the luxury of the elucidation of precise

kinetics of change (in terms of assigning rate

constants and orders of reaction). One could

also take issue with the recommendation that

testing to determine modes of degradation

should take place during Phase I clinical trials.

In the opinion of this reviewer, this is rather late

in the day, particularly if the findings suggest

that an alternative salt form or polymorph may

be more suitable for development, or that a

specific degradation product requires qualific-

ation in animal safety programmes. However,

there is often no right or wrong time to address

such issues and case-by-case judgement may

be necessary.

Topics such as method transfers are interest-

ing but their relevance to stability seems rather

tenuous. The regular use of the term ‘potency’

rather than ‘assay’ will also irritate readers

familiar with the precise context in which it

should be used (it should be adopted only when

a biological assay is involved).

Regulatory requirementsThe main focus of the book concerns regulatory

requirements, particularly those elaborated by

Book review