Regulatory Audit
observations/nonconformities with respective to DATA Integrity and Quality Assurance
System with regards to training, cleaning validation, breaches of data integrity
Sixteen (16) reports of GMP non-compliance were issued in 2015 and
published by European Authorities on the EudraGMDP web site. Inspections may
have been conducted months earlier. Within that group, eleven (11), 69%, cited
deficiencies in the category of data
management / data integrity. This may be an incomplete listing because
the competent authorities are not required to post the summary reports for
non-compliant inspection outcomes. These reports are summaries, rather than
copies of the reports, and thus are more limited in detail than a US form 483
or warning letter. The reports may be found at the Eudra GMDP portal.
This article may helps to learns about the GMP Violations or Non Compliance with landscape scope of live examples.
Nature of Non
Compliance:
1.
Wockhardt Limited:
1. A critical deficiency was cited with regards to data integrity
of GMP records, entries were seen to be made when personnel were not present on
site, and documentation was seen that was not completed contemporaneously
despite appearing to be completed in this manner.
2. A second critical deficiency was cited regarding potential
product contamination, this included the use of inappropriate materials close
to product e.g. asbestos coated PTFE seals for centrifuge manways.
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3. A major deficiency was cited with regards to equipment and
facility, maintenance, design and qualification. Examples included,
inappropriate pressure differentials that were not in line with the original
design but had not been changed using change control, cleaning validation that
was not sufficiently robust to confirm cleaning practices and maintenance
issues, such as the failure to spark test glass lined reactor vessels for
integrity especially following maintenance.
2. North China Pharmaceutical Group Semisyntech Co., Ltd
Overall, 17 deficiencies were observed during the inspection,
Including 2 Critical and 4 Major deficiencies:
[Critical 1] Manipulation and falsification of GMP documents
(rewriting of records with change of content, an inconsistency of signatures
and date in many records, etc.) were observed in different department;
[Critical 2] Lack of data integrity in the QC laboratory (No access
control, inadequate traceability and archiving practices, no audit trail, no
restriction on the deleting of data, etc.) and falsification of the analytical
results for residual solvents;
[Major 1] Risk of
contamination in grade B area;
[Major 2] The change control related to (i)- the change of the
identification number of some manufacturing equipment and (ii)- the merger
project of NCPC semisynthec and Hebei Huari was found deficient;
[Major 3] Lack of documentation management, control, and retention
of superseded or obsolete version;
[Major 4] The company personnel was not adequately trained in GMPs
as evidenced by the critical and major deficiencies identified during this
inspection.
3.
Huzhou Sunflower
Pharmaceutical Co., Ltd
Overall, 27 deficiencies were observed,
including 1 critical
deficiency and 4 major deficiencies:
[Critical 1] The controlled area and the equipment that were used
for the final synthesis step in the manufacture of Povidone Iodinated, namely
the complexation reaction of Iodine with Povidone K30, presented a risk to the
patients due to contamination issues with particles and degradation products ;
[Major 1] Materials and quality documents were found at a scrap
yard outside the main building of the company as well as inside the
neighbouring company’s building without any written justification ;
[Major 2] The purified water production and distribution systems
were deficient (presence of a dead-leg, replacement of conductivity controllers
without formal change control, mistakes in calibration documentation, etc.) ;
[Major 3] Issuance of 2 different Certificate of Analysis in a
Batch Record of Povidone K30 without an appropriate deviation management;
[Major 4] Deficient IR spectrophotometer management (no user
requirements prior to acquisition of the equipment, no evidence that the
instrument was suitable with its intended use, no evidence that the instrument
was belonging to the inspected site).
4.
Polydrug
Laboratories PVT. Ltd
Overall, 17 deficiencies were found,
5 Major consisting in: -
1. Customer complaints
deliberately unregistered in the official logbook –
2. Storage of quality documents in an
uncontrolled location,
3. Involving staff from QC, QA, maintenance and
production –
4. Deficient management
of paper documents –
5. Deficient management
of the computerised system - Failure to address risks of cross contamination
for APIs sent out to micronisation subcontractor.
6. The combination of
these major deficiencies represents a critical deficiency leading to a
potential risk for the patient.
5. Wuxi Jida Pharmaceutical Co., Ltd
The inspection was performed by GMP inspectors in relation to the
manufacture of sterile glutathione sodium lyophilised object of a variation.
The inspection was focused on site 1 and production workshop number 3.
During the inspection 28
deficiencies were found, 15 of which were rated as major deficiencies.
Major Deficiencies: In many production steps deviations were found
regarding the sterility assurance and a risk of contamination of the product:
a) Sampling room (deviations 14-15-16): the changing room was not
designed in a suitable way to minimize the risk of contamination; the
differential pressure between the areas maintained at different cleanliness
grade was not monitored; the garments procedure was not in accordance to the
principle of classified areas;
b) Production areas
(deviations 19-20-21-24): the pressure differential between adjacent areas at
different cleanliness grade was not in compliance with the guidance value of
the European good manufacturing practices; the maintenance and cleaning
conditions of some production rooms were poor and not adequately handled; the
particle counters in B class grade (i.e. freeze-dryers and capping room) were
unsuitable located for the intended use; the API transfer from the mixer to
aluminum tin did not exclude a risk of API contamination.
c) Validation (deviation 7
from letter a to j): the validation approach for different activities was not
correctly performed according to the GMP requirements and validation reports
were not detailed (warehouse temperature mapping; holding time for
sterilization of tools; stay-time in UVpass box; maximum number of filters
sterlisation (20) validation for the moist heat sterilizer used for the rubber
stopper sterilization; validation for the dry heat steriliser used for the
aluminium tin sterilisation; validation for LAF in weighing room; validation
for the HVAC of the sampling room; validation for front-freezing room
classification; validation report for the process simulation namely maximum
filling time of loading the bulk product in freeze-dryers and maximum time of
transferring API from mixer to aluminum tins and capping.
d) Packaging and labeling
(deviations 5-10-11-13): the management for the container closure system for
sterile glutathione sodium freeze-dried was found lacking in some tests to
guarantee the sterility assurance of the product; a “wrong“and not-updated
label was used as a standard to verify the shipping labels of API; in the API
warehouse, the aluminum tins of sterile API were not sealed; the aluminum caps
were not identified with a batch number loosing traceability.
e) Laboratory testing (deviation 28): some deviations were found
for the IR instrument, in particular the IR software had not a controlled
access via ID and password and it was not forbidden to copy and rename a file.
f) Personnel behavior (deviations 2-7i(ii)-18-19): during the
inspection, the inspectors’ team received inconsistent and conflicting answers
on the same topic from both personnel and management; sometimes the answers
seemed to be modified according to the inspectors’ requests. The documentation
was showed in an ambiguous way as the examples: some layouts were replaced;
some documentation was unrelated to the topic. Finally management did not
comply with the clothing procedure during the inspection tour
6. Parabolic Drugs Limited
The quality
management system was found to be seriously uncontrolled and deficient in all
“Principles” (except principle 2.13 and 2.14) reported in the EUGMP
requirements as evidenced by critical and major deviations found in the
following areas: inadequate storage and control of documents and samples and
material, falsification of documents and data, integrity and security of data
in the QC laboratory, Change Control, Deviations management and Risk
management.
In total 27
deficiencies were found:
3 classified as
Critical were found in the area of Documentation management system,
Falsification and Security and integrity data;
7 classified as
Major deficiencies were found in the area of QC, Personnel, Documentation and
Change Control.
7. Jinan Jinda Pharmaceutical Chemistry Co., Ltd
In total 18 deficiencies were identified by the inspection team,
one of them was classified as critical and six as major.
The critical observation was related to an unofficial and
non-controlled storage area containing mainly raw materials and finished
products which had been made inaccessible to inspectors as the door had been
removed and replaced with a panel fixed with screws to the wall, which during
the inspection the Company was requested to remove.
The material stored in this area was to be managed outside of the
Quality Assurance system and the investigation carried out by the inspection
team concluded there was a serious risk of data falsification.
One of the six major deficiencies was related to a very similar
issue, as access to a locked garage was given to the inspection team only hours
after requesting it. In both cases the explanations provided were not sound and
different versions were given during the inspection.
The remaining five major deficiencies were related to specific
aspects of the Quality Assurance System with regards to training, cleaning validation, breaches of
data integrity in the context of HPLC analysis, microbiological laboratory,
qualification of contract manufacturer of a key intermediate of Nitrofurantoin
production.
8. Cargill France
Overall, 14
observations were made, including 1 critical deficiency and 4 major deficiencies:
[Critical] The
management of semi-finished batches and of the mixing operations was deficient
and conformity of the final batches to specifications, notably Ph.Eur.
specifications, could not be guaranted.
[Major 1] The site
had been manufacturing an active substance without ANSM authorisation.
[Major 2] The change
control related to the suppression of one filtration step in the active
substance manufacturing process was deficient.
[Major 3] The
manufacturing of the active substance had not been made using master production
instructions and no batch production records had been established.
[Major 4] No review
of batch production records of critical process steps had been done before
release of the active substance for distribution.
7 observations are
related to lack of traceability, risks of contamination induced by the absence
of cleanliness in the production environment, very bad condition of the
production equipment and insufficient equipment cleaning procedures.
The inspection’s
observations also apply to the manufacture of pharmaceutical excipients and
starting materials that are intended to be used as ingredients in cosmetics and
medical devices, which are manufactured under the same conditions as the active
substance
9. Iason Utakua Srl
During the inspection 19 deficiencies were identified, 3 of them
were rated as critical deficiencies and 11 as major deficiencies.
The main deficiencies were related to the Quality Management
and the Quality Assurance Systems also in terms of sterility assurance
and risk of contamination/defects of the final product.
One critical deficiency was related to failure to fully investigate
and document out-of-specification results for microbiological environmental
monitoring in class A isolator and class B/C surrounding areas, in manufacture
of radiopharmaceuticals aseptically prepared. The company didn’t carry out an
appropriate and full-scale investigation to determine what caused the OOSs. An
appropriate level of corrective action analysis was not applied during the
investigation and the true root cause(s) were not determined.
Failure to address the root cause due to ineffective CAPA revealed
a lack of the quality assurance framework system.
Another critical deficiency was reported with regards to production
processes which were considered not satisfactory controlled: it was found that
for the manufacture of some batches of the radiopharmaceutical Pcolina
(Iasocholine) a non suitable reagent was used (expired dibromomethane).
Moreover, for some batches of released RPs master batch documents
were incomplete.
No adequate review by QA or QP.
Furthermore, preparation of the starting material set for
radiopharmaceuticals was performed in condition not appropriate to guarantee an
adequate level of chemical and microbiological containment.
The inspection’s team has rated also as critical the observation
related to the number of personnel in force to the manufacturing site, which
were considered not appropriate to conduct all the activities in accordance
with the GMP and to maintain the quality management system and its
effectiveness. The remaining major deficiencies were related to specific
aspects of the Quality Assurance System with regards to PQR assessment,
revalidation and recalibration of critical equipment, data integrity in the context
of HPLC management, storage of materials and documentation system
10.
AstraZeneca Pharma
The API
manufacturing process was not acceptably validated and was not under control
after the validation. The concerned batches have been sent to the EEA (Sweden)
and to a third country (China).
During the
inspection, 24 deficiencies were found. None of the deficiencies was critical
but 4 were major.
The 4 major
deficiencies were found in the areas of documentation routines and data
integrity (2), design and maintenance (1), validation (1). After three CAPA
responses from the company the major deficiency regarding validation still
remains.
11.
Minshing Group
Shaoxing Pharmaceutical Co. Ltd.
Nature of
non-compliance : Overall, 18 deficiencies were observed during the inspection,
including 2 Critical and 4 Major deficiencies:
[Critical 1] Falsification of source of API (Thiamphenicol): Repackaging, relabeling and
selling of purchased API from a non-GMP company (Zhejiang Runkang
Pharmaceutical Co.Ltd.) as if manufactured in-house;
[Critical 2] Praziquantel manufactured
according to CP process/grade was released as USP process/grade without a full
traceability of the testing activities ;
[Major 1] The
maintenance and the cleaning operations of the manufacturing line used for the
production of Praziquantel (API) were found deficient;
[Major 2] The pipes design of some equipment
used for the manufacturing of Praziquantel, the handling of change related to
these equipment and the instruction used for the transfer of the intermediate
solution using nitrogen were found deficient ;
[Major 3] The hoses
used for unloading of solvent were not identified, had no cleaning status and
were stored on a dirty floor of an area not mentioned in the general layout of
the site;
[Major 4] There was
no procedure in place for audit trail and there was no effective audit trail in
place to determine any change or deletion of the chromatographic raw data.
The
audit trial function including the administrator profiles was enabled for all
the QC staff. The inspection was performed in the framework of WHO
prequalification of medicines programme for the manufacture of Praziquantel
API.
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“
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privacy of any person. The views expressed or information supplied through this
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intend to defame, insult or, cause loss or damage to anyone, in any manner,
through this article.”
Author: Mahender Nagaraju
www.gmpviolations.com
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