U.S. patent application number 11/921216 was filed with the patent office on 2009-01-22 for method for the provision of clinical trial products.
This patent application is currently assigned to NYCOMED GmbH. Invention is credited to Rango Dietrich, Gabriele Emser, Michael Lange, Jutta Pfeiffer.
Application Number | 20090020442 11/921216 |
Document ID | / |
Family ID | 36939021 |
Filed Date | 2009-01-22 |
United States Patent
Application |
20090020442 |
Kind Code |
A1 |
Dietrich; Rango ; et
al. |
January 22, 2009 |
Method for the Provision of Clinical Trial Products
Abstract
The present invention relates to a method for the provision of
clinical trial products and packaging of clinical trial products
using RFID units in the context of clinical trials.
Inventors: |
Dietrich; Rango; (Konstanz,
DE) ; Emser; Gabriele; (Kreuzlingen, CH) ;
Pfeiffer; Jutta; (Langenargen, DE) ; Lange;
Michael; (Konstanz, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
112 South West Street
Alexandria
VA
22314
US
|
Assignee: |
NYCOMED GmbH
Konstanz
DE
|
Family ID: |
36939021 |
Appl. No.: |
11/921216 |
Filed: |
June 8, 2006 |
PCT Filed: |
June 8, 2006 |
PCT NO: |
PCT/EP2006/063022 |
371 Date: |
December 21, 2007 |
Current U.S.
Class: |
206/232 |
Current CPC
Class: |
G06K 7/0008 20130101;
G06K 19/0723 20130101; G06K 19/04 20130101; G06K 7/10435
20130101 |
Class at
Publication: |
206/232 |
International
Class: |
B65D 71/12 20060101
B65D071/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 8, 2005 |
DE |
10 2005 026 563.4 |
Claims
1. A primary packaging for medicaments in the form of a blister
comprising a RFID unit placed on a metal free area of the
blister.
2. The primary packaging according to a claim 1, wherein the
blister comprises an aluminium layer and wherein part of the
aluminium layer has been removed to form a metal free area.
3. The primary packaging according to claim 1, wherein the RFID
unit is connected to a tag, and the tag comprises a printable
carrier material and a self-adhesive layer.
4. The primary packaging according to claim 1, wherein the antenna
of the transponder of the RFID unit is arranged in close or direct
contact with the metal surface of the blister on the metal free
area.
5. The primary packaging according to claim 1, wherein the
medicament is a clinical trial product.
6. A method for the provision of clinical trial products in the
context of clinical trials, comprising the following steps: (a)
applying one or more RFID units to a primary packaging of a trial
product, (b) arranging one or more primary packagings, obtained
after step (a), inside a secondary packaging, (c) applying one or
more RFID units to the secondary packaging obtained in (b), (d)
arranging one or more secondary packagings, obtained after (c),
inside a common outer packaging, (e) optionally applying one or
more RFID units to the outer packaging, and (f) recording all the
packaging components by means of the RFID units, wherein the
primary packagings comprise a package according to claim 1.
7. A test specimen shipper comprising an outer packaging which has
an RFID unit and contains one or more secondary packagings, the
secondary packagings each having one or more RFID units, the
secondary packagings containing one or more primary packagings, and
the primary packagings having one or more RFID units and wherein
the primary packaging comprises a package according to claim 1.
8. The test specimen shipper according to claim 7, in which one or
more trial products are contained in the primary packagings.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The invention relates to a method for the provision of
clinical trial products and clinical trial products carrying RFID
units in the context of clinical trials.
PRIOR ART
[0002] Radiofrequency identification (RFID) is a technology
affording new possibilities of automation in many fields of
application, including in the pharmaceutical industry, for example
in the logistics involved in carrying out clinical trials. The
transponders used in RFID technology are usually composed of a
microchip for storing data, and of an antenna for transmitting
data.
[0003] Clinical trial products, in contrast to drugs that are sold
on the market after approval, are distinguished, among other
things, by the fact that a plurality of packaging hierarchies have
to be established on an individual patient basis depending on the
design of the clinical trial. The "box within a box within a box
within a box" principle applies. Here, very different products can
be contained at different "box depths" within an outer
packaging.
[0004] In addition, the packaging is carried out according to the
randomized clinical trial protocol, and the specimens have to be
blinded, that is to say be packaged in an indistinguishable manner.
In addition, a tamperproof seal is often required in order to
indicate unauthorized opening of the packaging.
[0005] The difficulty that arises now is that, on the one hand, the
relevant regulations (e.g. GMP Annex 13) require that a check be
made to ensure that the blinding has been done correctly. In other
words, after the packaging has been carried out, the test specimens
have to be checked in respect of their identity and correct
blinding, so as to prove that test medication or reference
medication or active drug or placebo has been correctly allocated
to the correct patient (according to the randomized allocation
according to the trial protocol). On the other hand, this check can
only be done by specimens being removed from all of the blinded
packages and examined. For this examination, it is generally
necessary to open the package, in other words to break the
tamperproof seal. The check can therefore also only be carried out
on specimens which in terms of quality and number have to be
representative of the overall collective and, as these tests are
destructive ones, these specimens cannot afterwards be returned to
the collective. This results in gaps in the patient numbers, which
in turn disrupt the conduct of the clinical trial.
[0006] A method would therefore be desirable which can be used on a
completely closed and sealed packaging without destructive testing
and visual contact (such as, for example, in the case of a barcode;
for this the package would have to be opened in order to record the
individual components) and not just on one specimen but instead on
the entire collective so as to rapidly and reliably identify, and
thus guarantee, the correct composition of all the component parts
of the trial medication across all packaging levels and their
correct allocation to the patient numbers in accordance with the
randomization protocol of the clinical trial.
[0007] In connection with such a method, it ought also to be
possible to rationalize the legally prescribed specimen count
carried out after completion of the study (also called pill
counting).
[0008] GB 2342203 describes a method for drug packaging, for use in
carrying out clinical trials. Containers are provided which, for
example, have an RFID tag and are filled with a specific drug that
is to be packaged. The identity of the container and the identity
of the drug located in the latter are stored in a database,
together with data for inscriptions, and a tag containing the
information stored in the database is applied to the container. The
risk of applying the wrong tag is thereby avoided.
[0009] WO 01/94016 describes a sample container comprising a holder
for receiving a sample, and an RFID unit (radiofrequency
identifier) comprising an antenna for transmitting or receiving
radiofrequencies, and an integrated circuit chip connected to the
antenna, the RFID unit being arranged on a carrier, and the carrier
being connected to the holder for receiving the sample. The holder
is intended in particular for use in clinical trials. The carrier
is a cylinder which is made of non-metallic material and has an
RFID tag wound round it. The cylinder itself is preferably made of
plastic which is connected as cap or directly to the aerosol
container by means of synthetic resin adhesive.
[0010] US 2004/0046020 is related to a medication-dispensing unit
which is provided for tracking medical product having a Radio
Frequency Identification (RFID) tag uniquely associated
therewith.
[0011] EP 1561689 is related to process control and documentation
of packaging of individual packages each having an individual
package transponder, comprising characterizing information capable
of documenting the package with a first writing unit registering in
each transponder, reading information from the transponders before
the individual packages are packaged, and controlling commencement
of operations of processing in response to correct information.
[0012] DE 10010140 is related to an apparatus for preferably
automatic handling and/or processing of objects, in particular in
the field of medical technology, having at least one processing
station and one object carrier for bringing the object to the
processing station, optionally through the processing station, and
away from the processing station, is characterized in that the
object carrier has a code; that data concerning the object and/or
the handling or processing of the object can be assigned to the
code; and that the data can be read or retrieved by way of the
code.
DISCLOSURE OF THE INVENTION
[0013] Surprisingly it has now been found that the above-described
desirable method for the provision of test specimens in the context
of clinical trials can be realized by means of RFID. By application
of pre-coded RFID tags to all packaged medication components of the
primary and secondary packaging levels (in other words the actual
medication and all of the surrounding packagings) and by suitable
arrangement within the packaging, it has been shown that it is
possible to guarantee complete recording of all the trial products
contained in a packaging.
[0014] It is thus surprisingly possible, in light of the problems
set out above, to make a complete identity check of all the
medication components of clinical trial products even at
considerable box depths, on this basis to achieve a parametric
release of the medication under the aspect of "Identity check for
correct randomization" according to GMP Annex 17, and thereby
dispense with the analytical chemistry identification check and
determine rapidly and in a contactless manner, at the time of
return of medication at the end of the study, which medication
packages have been returned, and to forward these for counting. The
rationalization effect in conjunction with the improved quality
(since the identity check no longer has to be restricted only to
the tested specimen and instead applies to the entire collective)
and accelerated execution of the legally prescribed procedures is
enormous.
[0015] The subject of the invention is therefore a method for the
provision of clinical trial products in the context of clinical
trials, comprising the following steps:
(a) applying an RFID unit to the primary packaging of a trial
product, (b) arranging one or more primary packagings, obtained
after step (a), inside a secondary packaging, (c) applying an RFID
unit to the secondary packaging obtained in (b), (d) arranging one
or more secondary packagings, obtained after (c), inside a common
outer packaging, (e) optionally applying an RFID unit to the outer
packaging, and (f) recording all the packaging components by means
of the RFID units.
[0016] According to the invention, trial products are to be
understood as presentation forms of active substances or placebos
which are tested in a clinical trial on humans or are used as
comparison products or are employed to generate certain reactions
in humans. According to the invention, this term covers drugs that
are not approved and also approved drugs when these are used in the
context of a clinical trial on humans or animals in a presentation
form other than the one that has been approved or for an indication
that has not been approved or for gaining additional information on
the approved drug. Examples of presentation forms that may be
mentioned are solid oral forms (e.g. tablets, capsules, pellets),
inhaled forms (e.g. aerosol formulations, dry powder for
inhalation), presentation forms for parenteral administration (e.g.
infusions, injections), semi-solid forms (e.g. ointments, creams,
suppositories) and transdermal therapeutic systems.
[0017] Primary packaging, according to the invention, is to be
understood as the container or other form of packaging which is in
direct contact with the trial product. Examples that may be
mentioned are blister packs, cartons, tubes, bottles, ampoules,
stoppered vials, metered dose inhalers, drug powder inhalers,
sachets and sealed pouches. Secondary packaging, according to the
invention, is to be understood as a packaging in which one or more
identical or different primary packagings are received. In general,
secondary packagings are cardboard boxes or folding boxes in all
conceivable formats, wall thicknesses and designs, colours and
surfaces, for manual and automatic construction and delivery, blank
for subsequent tagging, or pre-printed.
[0018] According to the invention, the arrangement of primary
packagings in a secondary packaging is preferably done in an
ordered manner. It has proven advantageous in this respect if the
surfaces of the primary packagings that comprise a tag according to
the invention are oriented as far as possible parallel to one
another (also stacked one on top of another) and are not
perpendicular to one another. This is preferably done by applying
the tag always on the same side of the primary packaging and
correspondingly arranging the units in the secondary packaging. If
the primary packaging is round (e.g. bottles), particular attention
must be paid to the described arrangement in the secondary
packaging, because, in the event of rotation of the round
containers in the secondary packaging, the tag according to the
invention may end up in an unfavourable (i.e. non-parallel)
orientation relative to the other components of the secondary
packaging, thus making recording of the units difficult. According
to the invention, one or more identical or different primary
packagings can be received in a secondary packaging.
[0019] According to the invention, outer packaging is understood as
packaging in which one or more identical or different secondary
packagings can be received. The arrangement of the secondary
packagings in a common outer packaging is preferably done in an
ordered manner. Care must be taken to ensure that the surfaces of
the boxes of the secondary packaging that comprise a tag according
to the invention are oriented as far as possible parallel to one
another (also stacked one on top of another) and are not
perpendicular to one another. This is done by applying the tag
always on the same side of the box and correspondingly arranging
the boxes in the outer packaging. It is also possible to receive
one or more outer packagings with or without RFID units in any
desired additional outer packagings. This results in a test
specimen pack also called test specimen shipper or RFID specimen
shipper.
[0020] The RFID unit (according to the invention also called
transponder) comprises, according to the invention, a microchip
(hereinafter referred to as chip) for storing data, and an antenna
for receiving or transmitting data. At the time of production, the
microchip is given a globally unique code and is connected to the
antenna, and both can be applied on a common carrier. An energy
source can also form a component part of the RFID unit. Various
RFID units are commercially available which operate with defined
frequencies in the range of 50 KHz to 2.5 GHz. The 13.56 MHz
systems are particularly suitable for applications with metals and
liquids. Examples that may be mentioned are commercially available
systems such as the OBID I-scan HF reader family with the
corresponding transponders from Philips, Infineon and Texas
Instruments.
[0021] According to the invention, RFID units are preferred which
are connected to a tag. The tag is preferably of paper,
polyethylene or of other carrier materials known to a person
skilled in the art and has a self-adhesive layer. The tag is
preferably structured such that the RFID unit and the tag form one
unit, the RFID unit being applied on the rear/lower part of the
tag, between carrier material and adhesive layer.
[0022] In one embodiment of the invention, in particular for
application on metallic substrates, the RFID unit is positioned
between the tag and the adhesive layer. To do this, the adhesive
layer of the tag can be lightly foamed (0.2-0.4 mm) so that the
raised parts of the RFID unit can be pressed into the adhesive
layer. This means that the tag can be left with as large as
possible a surface area to be printed on.
[0023] The tag containing the RFID unit can be printed with the
variables typical of the study, and the microchip contained in the
RFID unit can be coded with a numerical or alphanumerical code.
According to the relevant regulations (e.g. GMP Annex 13), this
code is an admissible replacement for the indication of the batch
reference for demonstrating in clinical studies which patient has
received which medication from which clinical study, without
unblinding the study in order to do so. It is therefore necessary
to give the code a structure that not everyone can understand. The
code can then be used, for example, for tracing the correct
randomization and the distribution chain. The code is preferably
generated by a higher-order IT system (e.g. MES=manufacturing
execution system) and is linked logically to the associated
packaging step. The link is generally created in the packaging
procedure, by a tag according to the invention with RFID being
assigned to a certain medication or patient package and affixed.
The code can then contain, for example, the patient number, the
packaging level, the medication, the study title, the name of the
trial centre, etc. in encrypted form. In manufacturing execution
systems, the code can be generated in conjunction with the creation
or drafting of the packaging directions (on paper, or
electronically, then called electronic batch records) from the
details of the packaging design.
[0024] Alternatively, the RFID chip contains only the globally
unique code applied already during the production of the chip,
which code initially has no relationship to the packaging
sequences. In the latter case, the code has to be read out at the
time of application of the tag and, for each individual packaging
step, has to be linked logically in the higher-order information
management system to the associated packaging step.
[0025] The units provided with a (pre-coded or system-coded) RFID
are then applied to the packaging of the respective packaging
hierarchy level (primary packaging, secondary packaging or outer
packaging). This is preferably done by means of the self-adhesive
layer of the tag containing the RFID unit being affixed to the
package. This procedure is repeated for as many times as there are
different packages at different packaging depths in accordance with
the design of the clinical study. A packaging collective of greater
or lesser complexity is obtained consisting of several components.
According to the invention, one or more RFID units can be applied
to a primary packaging, secondary packaging or outer packaging.
[0026] According to the invention, the packaging components are
recorded by means of the RFID units preferably via a reader, with
which the data stored on the RFID units can be read out and
transferred to an electronic database. This can be stored in a PC
(personal computer) or be part of a higher-order information
management system.
[0027] Since all the components carry an RFID unit, all of the
components contained in the packaging collective can now be
identified in one operating step (i.e. simultaneously) without
destructive opening of the packaging and without any visual link.
Since each unit acquires, via the code, the information concerning
for which patient the respective package is intended and shows
which medication it contains, the sum of the individual information
items on the packaging level can be used to characterize the entire
packaged collective. Non-destructive testing for correct blinding
and randomization which in terms of its expressiveness goes far
beyond the results of an analytically tested random sample
(destructive testing). Since the whole collective can be recorded
and the correct assignment of the code is effected already in the
respective packaging step and a plausibility check is made there,
it is possible in this way to determine and prove the correct
allocation of the packaging units in the overall collective. This
process of tests and proof of correctness on the basis of data
acquired during the production process is called "parametric
release".
[0028] Since the data of the individual packaging components
including the encrypted information on patient number, study number
and trial centre number are contained in the code, this information
can be used at the end of the trial for evaluation purposes. In
contrast to commercial goods, test specimen packagings are returned
after use in the empty or opened state. These used packages are
used to evaluate how much medication the individual patient has
taken and on this basis to decide whether the patient can or cannot
be included in the assessment of the study. The necessary recording
of each individual package and the allocation to the study and
patient can be rationalized by automatic recording of the
information stored in the RFID. Since in contrast to the barcode,
no visual link is needed with RFID, a complete shipment unit with
several hundred patient packages can in theory be recorded
simultaneously, without each individual package having to be
separately handled (as in the case of a barcode).
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIG. 1a shows components of an RFID system.
[0030] FIG. 1b shows a block diagram of an RFID unit with memory
function.
[0031] FIG. 2a shows a tag with an RFID unit.
[0032] FIG. 2b shows the layered structure of an RFID unit with
foamed spacer layer (section IIb-IIb in FIG. 2a).
[0033] FIGS. 3a-3d shows different secondary packagings in an outer
packaging (test specimen pack or RFID specimen shipper).
[0034] FIG. 4 shows the recording of all the packaging components
of an RFID specimen shipper.
DETAILED DESCRIPTION OF THE INVENTION WITH REFERENCE TO THE
FIGURES
[0035] FIG. 1a shows a schematic representation of the component
parts of an RFID system. Data stored on RFID units (2) can be read
out via a reader (1) and transferred into an electronic database
(3). This can be stored on a PC (personal computer) or be part of
an information management system.
[0036] The reader (1) transmits radiofrequency energy to the RFID
unit or receives radiofrequency energy from there. The reader can,
for example, be a long-range RFID reader with gate or tunnel
antenna. A particularly effective application for bulk recordings
with critical media (metals, liquids) is the long-range reader for
13.56 MHz systems with plexed 3D tunnel antenna. The reader
generates a high-frequency electromagnetic field which at the
transponder level induces an oscillation circuit whose resonant
frequency corresponds to the transmit frequency. By means of load
modulation at transponder level, the amplitude of the voltage on
the oscillation circuit also changes. This principle is used to
transmit data in both directions. The RFID transponder (2) is made
up of an antenna (2a) connected to a microchip (2b). The microchip
is composed of the following 4 modules as HF interface (2c),
address and safety logic (2d), ROM (2e) and EEPROM (2f). In the
ROM, the RFID transponder is inscribed with a unique ID. (Name,
manufacturer, UID 64 bit-92 bit). The EEPROM serves to record data
(384 bit-7 kbit). FIG. 1b
[0037] FIG. 2a shows an RFID unit (2) which is connected to a tag
(4). The tag is of paper, polyethylene or of any other customary
carrier materials that can be printed on and are known to a person
skilled in the art and it has a self-adhesive layer. The tag is
structured in such a way that the RFID unit and the tag form one
unit, the RFID unit being applied on the rear part of the tag,
between carrier material (4a) and adhesive layer (4b). In one
embodiment of the invention (in particular for use on metal
supports), the RFID unit (2) is positioned between the carrier
material (4a) and the adhesive layer (4b); to do this, the adhesive
layer (4b) of the tag is lightly foamed (0.2-0.4 mm), so that the
raised part of the RFID unit (2) can be pressed into the adhesive
layer. This makes it possible to leave free a large surface area
that can be printed on. The required texts can be printed onto this
surface area. The RFID unit (2) in this embodiment is a passive
13.56 MHz RFID unit (microchip connected to an antenna without
energy source) placed on a support film (2g). An example that may
be mentioned is the ISO Philips semiconductor transponder with
dimensions of 32.times.16 mm. This can be read out with a reader
(1) in the form of a 13.56 MHz long-range RFID reader with gate or
tunnel antenna.
[0038] In a first step, the required RFID unit is prepared in the
form of tags in accordance with the information which is stored in
a database or higher-order information management system for the
packaging unit that is to be produced in the context of the
clinical trial. The task of printing the tag can be undertaken by
an RFID thermal transfer printer (integrated RFID writer-reader)
which simultaneously prints the RFID tag, checks the functionality
of the RFID transponder and inscribes or reads out the transponder.
For example, in this process the UID(64 bit) of the transponder can
be read out and linked with the table entry for this tag in the
database of the management system. (RFID-UID and information on the
print content are linked in the database and can be utilized for
automatic checks).
[0039] As shown in the FIGS. 3a to 3d, primary packagings in the
form of bottles (5a) blister packs (5b) and aerosol containers (5c)
and secondary packagings (6a, b, c) are organized according to the
packaging directions, provided with the corresponding RFID tags 7
a, b, c and then checked for identity and the correct numbers. In
connection with blister packs (5b) which contain suitable metals
such as aluminium as components (aluminium blisters) the RFID-tags
(7b) are preferably placed on the blister on a metal free area (5d)
such that there is no overlapping of the antenna of the transponder
with the metal surface of the blister. Such metal free compartment
can for example be obtained by partially removing the aluminium
layer of an aluminium blister. It is advantageous for the antenna
of the transponder to be arranged in direct or close contact with
the metal surface of the blister, since a strengthening of the
antenna action can in this way be achieved.
[0040] The secondary packagings are organized according to the
packaging directions, provided with RFID tags 8a, b, c and then
checked for identity and the correct numbers on the basis of the
data stored in the RFID. The test specimen shipper 9, which can
likewise be provided with an RFID tag 10, is organized according to
packaging directions and then checked for identity and the correct
numbers. According to FIG. 4, in the final check the test specimen
shipper 9 is pushed into an RFID tunnel reader 11 and thus checked
for identity and the correct numbers. At the same time reference is
made to the database 3 of the electronic management system, and
complete documentation of all the GMP production processes carried
out on this product and its checks has to be verified by the head
of production and released.
* * * * *