Released by FDA: 1/11/01. Posted by FDA: 1/19/01
Dr. Thomas Aqvist
Plant Director Pharma Malardalen
S-112 87 Stockholm, Sweden
Dear Dr. Aqvist:
We have completed our review of the inspection of your Malardalen
sterile finished manufacturing operations which includes Swedish sites in
Stockholm, Uppsala and Brunna by Investigator Thomas J. Arista and Chemist
Robert D. Tollefsen during the period of June 26-July 12,
2000. The inspection revealed significant deviations from U.S.
Current Good Manufacturing Practice Regulations (Title 21 CFR, Parts 210
& 211) in the manufacture of sterile pharmaceutical
products. The deviations were presented to you on an
Inspectional Observations (FDA-483) form, at the close of the
inspection. These CGMP deviations cause your pharmaceutical
products to be adulterated within the meaning of section 50l(a)(2)(B) of
the Federal Food, Drug, and Cosmetic Act.
Specific areas of concern include, but are not limited to:
1. The Malardalen operation uses both the [confidential, deleted by
FDA] System) and [confidential, deleted by FDA] network computer software
programs for materials and data management functions. The
[confidential, deleted by FDA] performs functions typical of a laboratory
information management system. The quality control unit uses
this program for disposition of materials, special studies, stability
testing programs. and generation of summary test reports. Once
material is dispositioned, [confidential, deleted by FDA] communicates
information to the [confidential, deleted by FDA] network program used by
warehouse and production personnel to control material in storage and
production. Both the [confidential, deleted by FDA] and
[confidential, deleted by FDA] network programs work in concert acting as
the sole source of information which controls and maintains the status of
raw materials and finished goods in the warehouse. Your
operations use these programs in a similar manner to control in-process
materials during manufacturing operations. These network
program systems are deficient in that:
a. The [confidential, deleted by FDA] network program lacked adequate
validation and/or documentation controls. For example:
• The system design documentation has not been maintained or
updated throughout the life of the [confidential, deleted by FDA]
software dating back to 1985 despite significant changes and
modification that have taken place. These include program code,
functional: structural design, diagrams, specifications, and text
description of other programs that interface with [confidential, deleted
• The program was not controlled by revision numbers to
discriminate one revision from the other.
• inadequate standard operating procedures to ensure that records
are included with validation documentation, maintained and updated when
changes were made.
• Significant deficiencies regarding documentation controls were
reported. Documents were either not dated, lacked a documentation
control number, were missing, were reported in pencil on uncontrolled
pages, or dates were crossed out without initials, dates, or
• There was no assurance that complete functional testing had been
preformed in the [confidential, deleted by FDA] system. For
example you failed to assess all historical testing and compare it with
current functionality to ensure that all current [confidential, deleted
by FDA] functionality has been adequately evaluated.
b. The [confidential, deleted by FDA] network program lacked adequate
validation and/or documentation controls. For example:
• The program uses a purchased custom configurable materials
management software package. The software validation
documentation failed to adequately define, update and control
significant elements customized to configure the system for the specific
needs of the operations. The following had not been
maintained or updated from original release/design specification dating
back to approximately 1985:
• Revision control system.
• Validation records did not address the order of libraries, which
• Structural and functional diagrams and design descriptions.
• Complete diagrams with text description identifying other network
programs which interface with [confidential, deleted by FDA]
• Deficiencies regarding documentation controls such as maintenance
of records, lack of review and approval of change control and other
• Inadequate standard operating procedures to ensure that records
are included with validation documentation, maintained and updated when
changes are made.
c. The wide area network also identified as the [confidential, deleted
by FDA] is used to connect network applications to local area networks
[confidential, deleted by FDA] at Malardalen operational facilities.
The [confidential, deleted by FDA] and [confidential, deleted by FDA]
network application at each site by departments using these programs to
perform their GMP function. Both the [confidential, deleted by
FDA] and [confidential, deleted by FDA] documentation were not included in
the [confidential, deleted by FDA] and [confidential, deleted by FDA]
validation efforts and therefore lacked adequate documentation controls.
Your response for the [confidential, deleted by FDA] acknowledges
that the system has not been maintained throughout its life and there are
gaps in the documentation. You indicate rather than expending resources on
reviewing validation documentation that in sonic cases is 15 years
old. you are looking forward to a replacement of the
[confidential, deleted by FDA] system with a new validated computer system
in the near future. In the interim your validation effort was
to review only the current system documentation with respect to the
Investigator’s computer concerns. You evaluated the
functionality and reliability of [confidential, deleted by FDA] by
comparing the printout of 21 US batches against source documents and no
errors were found. As a result you concluded that the
[confidential, deleted by FDA] system functions correctly and reliably and
has been validated. Your response fails to trace back to
source code, and the related software development cycle which establish
evidence that all software requirements have been implemented correctly
and completely and are traceable to system requirements.
Software is validated in its controlled development and in control of
ongoing maintenance of the software and its documentation throughout its
life cycle. You make no commitment to retrospectively put the historical
Your response for [confidential, deleted by FDA] indicates upgrading
[confidential, deleted by FDA] and [confidential, deleted by FDA] version
[confidential, deleted by FDA] installed during 1997 to version
[confidential, deleted by FDA] on or about December 2001 and inclusion of
corrective actions in version [confidential, deleted by FDA]. Also
you will continue to use, and complete a retrospective evaluation of
[confidential, deleted by FDA] on or about December 2000. The
inspection reports that the documents reviewed did not define the system
as being validated but was a qualification document for the [confidential,
deleted by FDA] version upgrade. The records did not describe
the custom configuration of the [confidential, deleted by FDA] system as
it is in place. Your response did not evaluate requirements or
trace changes to determine side effects. Further, your
response failed to address the issue of what sites are approved to use the
[confidential, deleted by FDA] application nor does it address defining
what restrictions will be in place for each site with respect to defining
what functions in MOVEX are approved for use at each site. In
order to consider a computer system to be validated, all elements which
make up the system must be clearly defined. Appropriate
systems definition documentation, properly updated when necessary
throughout the life cycle of the software, is part of the control and
ongoing maintenance of a computer program. Your response fails
to discuss extending the retrospective evaluation to other elements of the
system needing to be defined and controlled as part of the overall
It could be difficult to retrospectively validate a computer system if
there were changes and revisions that were not documented and the
cumulative affects of many revisions had not been assessed.
Lack of sufficient system documentation would make it impossible to
perform meaningful retrospective validation. FDA concludes
that the [confidential, deleted by FDA] and [confidential, deleted by FDA]
systems lack adequate validation and therefore are unacceptable for use in
the production of the drug products. Please indicate whether
you can perform a retrospective validation of the [confidential, deleted
by FDA] and [confidential, deleted by FDA] systems or rely in the interim
on manual operations that use source documentation until the the new
validated computer systems are functional.
2. The Malardalen local computer systems lacked adequate validation
and/or documentation controls. For example:
a. The [confidential, deleted by FDA] computer control alarm system
that monitors the air handling units temperature, humidity, and
airflow/pressure. the [confidential, deleted by FDA] water system, and
temperature of various freezers and refrigerators, lacked the
• Documentation demonstrating an adequately validated system, for
• System description.
• Functional tests of systems capability of simultaneously
monitoring normal operations and/or assessing alarm
• Description and definition of utility and equipment alarm
• Exact number of monitoring and/or controlling devices and
• Evaluation demonstrating accurate printed information.
• Adequate handling of records generated with inaccurate time
frames dating back sixteen years for mainframe computer clock and
three years for the local workstation computer clock due to Y2K
compliance related issues.
• Appropriate procedures to ensure that records are included with
validation documentation. maintained, and updated when changes were
b. The [confidential, deleted by FDA] alarm system that communicates,
records, and controls alarms related to air balance and temperatures for
production, warehouse and testing areas. storage rooms, and coolers,
lacked the following:
• Change control documentation approving-change in the
software. In addition, there was no qualification
[confidential, deleted by FDA] documentation for this change.
• Validation documentation failed to include complete and updated
system design documentation, and complete wiring/network diagrams to
identify all computers and devices connected to the [confidential,
deleted by FDA] system.
c. The [confidential, deleted by FDA] equipment’s computer
used for [confidential, deleted by FDA] filling operations which retains
equipment errors that occur during filling operations, lacked the
capacity to retain electronic data. After every 15th filling
operation, the information was overwritten due to the storage capacity
of the equipment’s hard drive.
3. Inadequate oversight by the Quality Control Unit (QCU) to ensure
that controls which impact the quality of sterile products are implemented
for manufacturing operations. For example:
a. The QCU failed to ensure that adequate procedures were put into
place to he tine and control computerized production operations,
equipment qualifications. documentation review and laboratory
b. The inspection reported numerous deficiencies regarding the lack
of approved procedures, failure to follow procedures, and inadequate
laboratory controls for documentation, storage and handling of samples
pertaining to the stability and environmental monitoring programs.
4. Inadequate [confidential, deleted by FDA] operating
procedures. For example:
a. Inadequate simulation (media fill) of [confidential, deleted by
FDA] filling operations:
• Failure to demonstrate that planned manual interventions during
media filling operations do not contaminate (negatively impact) the
media filled containers. Following these manual
interventions an unspecified number of units containing media near the
intervention areas are discarded and not incubated, which could result
in a bias of the media fill results.
• Discarding of unspecified numbers of media filled units
indicates that the media fill qualification would not be able to
substantiate that the contamination rate was not exceeded in order to
obtain the confidence level described in the validation protocol
[confidential, deleted by FDA].
b. Routes of contamination:
• Partially stoppered [confidential, deleted by FDA] filled
cartridges, were not kept under class 100 conditions during the
transfer process to the [confidential, deleted by FDA] or following
[confidential, deleted by FDA] for phase [confidential, deleted by
FDA] filling operations.
• Non-viable particulate monitoring was not performed in the
class 100 area immediately adjacent to the [confidential, deleted by
FDA] where partially stoppered filled vials are exposed.
• Cleaning and disinfection of [confidential, deleted by FDA]
panels positioned over the [confidential, deleted by FDA] filling zone
and class 100 areas were not documented. The panels are
removed semi-annually and there were no records demonstrating
• Unnecessary materials which lacked any records of disinfection
were observed in the [confidential, deleted by FDA] filling zone
(e.g., printer paper).
c. Inadequate personnel monitoring:
• Production personnel perform personal monitoring (fingers on
agar plate) on each other. An operator was observed spraying 70%
ethanol on gloved hands just before sampling and on two separate
occasions, operators were observed sampling with wet gloves.
d. Inadequate laminarity (smoke) studies:
• Laminarity of air flow was not adequately demonstrated during
dynamic conditions within class 100 [confidential, deleted by FDA]
e. Inadequate documentation of temperature distribution studies on
• There was no documentary evidence to support the validity of
the [confidential, deleted by FDA] placement and most difficult to
sterilize locations for the [confidential, deleted by FDA] chamber,
and the partially stoppered container transfer carts.
Regarding our response to 4a, we acknowledge your commitment to
corrective actions. However, some questions still
remain. Your response failed to demonstrate that a predetermined
number of units are removed during routine production and that each of
the specific circumstances under which these units are removed have been
clearly defined by written procedures. Please demonstrate
that the planned interventions during media tills were reflective of
actual production practices, procedural requirements, and worst case
conditions regarding the number of units discarded. Each
production intervention should be defined in detail within written.
approved procedures. Details relating to the intervention
should include the specific type. duration, extent, and number of units
removed. These details should be recorded in batch
production records. The activities defined by procedures and
documented by production records may then be simulated during media
fills in a manner that justifies the worst case production conditions
permitted in actual operations.
5. Inadequate maintenance of equipment and utilities. For
a. Inadequate diagrammatic representation of utility systems:
• The air handling system’s diagrams did not accurately
describe or reflect the air system such as the EU rated filters and
• The drawings that illustrate particulate classifications of
production areas were not accurate. An area used to handle
[confidential, deleted by FDA] filled containers into transfer cans
was erroneously classified 10,000 instead of 100.
• There were no Isometric drawings for [confidential, deleted by
FDA] water system that supplies [confidential, deleted by FDA] water
to the [confidential, deleted by FDA] system.
• .An outdated schematic (revision 2) of the [confidential,
deleted by FDA] water system hanging on a wall appeared to be in use
by the engineering maintenance staff. The current
schematic at that time was revision 4.
b. Plumbing system defects:
• There was no assurance that a pressure relief security valve
positioned above the [confidential, deleted by FDA] storage tank was
sealed closed to prevent ingress of microbial contamination into the
[confidential, deleted by FDA] storage tank.
• The plumbing system contained two manually operated by-pass
valves, positioned above [confidential, deleted by FDA] micron filters
which can permit unfiltered water to the [confidential, deleted by
FDA] feed tank. System qualification did not address use of
[confidential, deleted by FDA] water to the [confidential, deleted by
Our review also included your company's response letters to the FDA-483
observations dated July 20. 2000, August 17, 2000, September 4, 2000,
October 1, 2000, November 17 and 28, 2000, and December 11,
2000. We acknowledge that many corrections have been made, or
are in progress. Your response to observation 1 addressing the
[confidential, deleted by FDA] and [confidential, deleted by FDA] computer
validation and observation 4a, addressing media filled units was
inadequate as discussed above. Except for observations 1 and
4, the corrections when fully implemented appear to satisfactorily address
the deficiencies listed on the FDA-483. The CGMP deviations identified
above or on the FDA-483 issued to your firm are not to be considered an
all-inclusive list of the deficiencies at your facility. FDA
inspections are audits, which are not intended to determine all deviations
from CGMPs that exist at a firm. If you wish to continue to
ship your products to the United States, it is the responsibility of your
firm to assure compliance with all U.S. standards for Current Good
Please respond to this letter within 30 days of receipt.
Your response should include copies of procedures generated as well as
data collected in your correction to the deficiencies cited.
Please identify your response with CFN 9691013. Until FDA can
confirm compliance with CGMP’s and correction to the most recent
inspection deficiencies, this office will recommend disapproval of any new
applications listing your firm as the manufacturer of active
Please contact Edwin Melendez, Compliance Officer, at the address and
telephone numbers shown above, if you have any questions, written response
or concerns regarding these decisions.
To schedule a reinspection of your facility after corrections have been
completed, and your firm is in compliance with CGMP requirements, send
your request to: Director. International and Technical Operations Branch,
HFC-l34, Division of Field Investigations, 5600 Fisher’s Lane,
Rockville, MD, 20857. You can also contact that office by
telephone at (301) 443-1855 or by fax at (301) 443-6919.
Joseph C. Famulare
Division of Manufacturing and Product Quality
CC: Gary Harbour. Ph.D.
Assurance, Pharmaceutical Operations