GMP-News No. 35
23 June 1999
European Validation Conference
May 4-5, 1999
|The European Validation
Conference, organized by the European Compliance Academy (ECA) together with CONCEPT
HEIDELBERG took place in Berlin from May 4 5, 1999. Here representatives of
pharmaceutical companies, supervisory authorities and service providers discussed the
current status and trends as regards validation and qualification. Workshops on the topics
"Cleaning validation" and "Risk analysis by FMEA" rounded off the
The first paper was presented by Robert DELATTIN,
a GMP inspector in Belgium. He gave a general overview of the regulatory requirements in
the EU concerning validation. His announcement that the PIC Document PH 1/96
"Principles of Qualification and Validation in Pharmaceutical Manufacture" in
the revised version (PIC/S PR 1/99-1) has been valid since March 1 was received with
particular interest. Another surprise was Mr. Delattin's announcement that PIC/S PR 1/99-1
will form the basis of a 15th annex to the EC Guide. It is expected that this
annex will be available by the end of the year.
Conference site: Berlin-Köpenick
We would like to thank the UNIVALID company, Amsterdam
for supplying us with the photographs on this page.
Dr. Hermann ALLGAIER from Life
Sciences Meissner + Wurst GmbH, who was the moderator on the first day of the conference,
outlined the "FDA Requirements for Equipment Qualification and Process
Validation". He focussed in particular on the planned changes in the Code of Federal
Regulations (CFR) whose paragraphs 210.3, 211.22, 211.220 and 211.222 provide definitions
on the topics of validation, responsibilities as regards validation, information on scope
and documentation of validations and on method validations. He gave an especially
interesting description of the warning letters 97/98 which list the following validation
deficits in particular:
- Failure to apply scientifically sound or appropriate validation principles
- Deviations from validation protocols or procedures
- Lack of software validation for automated processing equipment
- Inadequate documentation
It was particularly remarkable that 75% of all validation deficits concerned active
substances (see Fig. 1)
Fig 1. Warning
Letters Fiscal Year 1997/1998 Percentage of Qualification /Validation Issues
BUREAU from Parke-Davis, spoke about Failure Mode and Effects Analysis (FMEA) as a tool
for risk analysis. He sees the major advantage of this method in the identification of
potential risks and their influence, and that the validation activities focus on those
items which have the greatest risk.
An FMEA is based on three
What happens if a failure occurs?
- Evaluation of the occurrence
What are the possible effects of this failure?
- Evaluation of the significance
Is the failure discovered when it occurs?
- Evaluation of the discovery
Each of these three questions is ranked on a scale of 1 to 5. The
individual scores are then multiplied with one another to yield a risk priority number
After the average RPN has been calculated, corrective measures are
initiated where the RPN exceeds the average. This improves the processes, and validation
activities are concentrated on high-risk items, i.e. a streamlining takes place. During
the post-conference workshop participants created an FMEA on the basis of practical
Christopher WOOD from Glaxo Wellcome spoke about the status of the
ISPE Baseline Commissioning & Qualification Guide. The Baseline is one of two
horizontal guides compiled together with the FDA in order to define the basic requirements
in consultation with the authorities. C. Wood differentiated between direct and indirect
systems, and systems with no influence on product quality. In all three cases Good
Engineering Practice (GEP) must be applied. These are established technical industrial
standards which are applied in adaptation to the regulatory requirements of the
In case of indirect systems commissioning takes place. This is a
comprehensive approach in which the planning, documentation and project management are
structured in order to maintain the prescribed design criteria and user specifications.
According to C. Wood, qualification activities (classical IQ, OQ)
are only necessary in the case of systems with a direct influence on product quality.
It is interesting to observe that the ISPE C&Q Guide avoids
using the term "Design Qualification" and uses instead the term "Enhanced
Design Review". The purpose of this is to avoid mix-ups with regulatory requirements
from the medicinal products sector. In this sector "Designing" is strictly
The goal is to submit the complete Guide to the FDA for review in
November 1999 so that it can be published as an official document in the first quarter of
the year 2000.
"Streamlining validation" and therefore also cost
reduction was also the topic of the second talk by Dr. Hermann ALLGAIER from Life Sciences
Meissner + Wurst GmbH. Using a complexity matrix, he demonstrated how extensive the
validation and qualification activities within a company are.
Overlooking the conference hall
|For Dr. Allgaier the
integration of qualification and validation activities is the key to increasing the
efficiency of validations.
This also includes in particular:
- The avoidance of duplication of work
- Focusing responsibilities
- Integrating and coordinating activities
He illustrated this using an Engineering Turnover Package Approach.
Dr. Hans H. SCHICHT of Contamination Control Consulting presented an
overview of the current and future regulatory requirements in Europe and the USA
concerning clean zones. He said that, in addition to the European body of regulations
(EC-GMP Guide) and the FDA aseptic Guideline and the U.S. Pharmacopoeia Draft Proposal,
the ISO standards play an important role. Particularly ISO 13408-1 gives particle limits
for rooms in which aseptic production takes place. A classification of rooms is also found
in ISO 14644-1. Information on the qualification of rooms is found in ISO/DIS 14644-4,
while requalification requirements are described in ISO/DIS 14644-2.
A proposal of Dr. Schicht's for the classification of rooms for
non-sterile manufacture was also discussed.
The last talk of the day was held by Walter TRAMPEDACH of CONCEPT
HEIDELBERG. His topic was entitled "The qualification of water systems in accordance
with the current GMP requirements". After a brief introduction to the options for
water systems W. Trampedach described the individual qualification stages (DQ, IQ, OQ, PQ)
in detail and provided practical examples as regards documentation.
Table Top Exhibition
|In his first presentation
W. Trampedach placed very great importance on the correct compilation of a DQ. Not only
does this reduce complaints as regards the executed shipment but it also simplifies the
IQ. He named the minimum SOP's necessary for operating a water system as follows:
- operation SOP
- inspection SOP
- calibration SOP
- cleaning SOP
- maintenance SOP
- sterilization SOP
- filter control SOP
In full agreement with the PIC/S PR 1/99-1 W. Trampedach sees the PQ
as the first step in the validation of the system.
W. Trampedach's statement that as of 1 July '99 the European
Pharmacopoeia, like the USP, will require conductivity measurements (at 20 °C not
more than 1.1µS cm-1) and TOC measurements (not more than
0.5 mg/l) was received with astonishment. Some wet chemical and physical tests,
however, will be dispensed with.
The first talk on the second day was held by Dr. Helmut BENDER of
Boehringer Ingelheim Pharma KG. He described what requirements from the point of view of
qualification and validation are placed on pharmaceutical development and production of
clinical samples. Dr. Bender dealt in depth with the "FDA Guideline on the
preparation of investigational new drug products". This states clearly that in the
production of batches for early clinical phases, the implementation of process validation
is only possible to a limited extent. For this reason, an expanded in-process and finished
product control is required. He named risk analysis as a decisive factor for being able to
implement validations economically. He considers possible tools to be FMEA (see above),
HACCP (Hazard Analysis and Critical Control Points) and HAZOP (Hazardous and Operability
Discussing during lunch:
W. Trampedach, Concept Heidelberg;
Anthony Trill, MCA
On the topic "Streamlining Validation" Dr. Bender
recommended in addition to compiling a master validation plan, also combining IQ and OQ to
form an "IOQ Plan". This reduces the amount of documentation and improves the
legibility of the documents since repetitions are no longer. Some participants criticized,
however, that this combined document presents the inspector with very much more data
during an inspection, with the danger of intensifying the inspection.
|Dr. Paolo VERARDI from Glaxo
Wellcome described in his talk the remodelling activities in his sterile powder filling
plant. Dr. Verardi described how a new building with new installations would have been
distinctly more expensive than the remodelling. The remodelling included arranging the
installations in cubicles, a new laminar flow concept, improved filling units and
controls, and a new instrumentation with a computer connection (PLC). All of these
measures not only contributed considerably improved process and work safety but also had
economic effects. For instance, the improved filling installation has saved $ 83,000
Dr. Verardi also presented the
bioluminescence method for determination of bacteria counts as part of monitoring. This
method, which is based on photoemission by released bacterial ATP by activation with
luceferin/luciferase proved very practicable. This was confirmed by comparison
measurements using the "classical" agar method.
According to Dr. Verardi, the great advantage of the bioluminescence
method lies in its rapidity. A significant result can be obtained already after only 10
JEATER from Validation in Partnership explained critical aspects in the validation of
solid and semisolid dosage forms. At the beginning of his presentation he spoke about the
FDA Guide to Inspections of Oral Solid Dosage Forms of May 1994. Using the hypothetical
example of " Dr. Faust's Tablets" he explained critical aspects of validation,
with reference to examples from GMP Trends in all cases. The process steps are
weighing-in, grinding, mixing, grinding, tableting, packaging (see Fig.)
Fig. Process for
manufacturing "Dr. Faust's Tablets".
| During mixing he considers it important that the validations include
determinations of mixing speed, mixing time and degree of filling. The data is confirmed
by means of samples taken at critical points. The content uniformity and the bulk and
tamped volume are examined. P. Jeater explained that it is important that a plan define
when, where and how samples are taken. The handling of the samples is also very important.
The more handling takes place, the more potential errors there are.
During grinding the analytical validation should also include distribution of particle
size. It should also be defined in the manufacturing specification. The samples are taken
after grinding, from the drums into which the ground material is filled. Samples are taken
from the bottom, the middle and the top of each drum. The samples are, however, taken at
different sites (north, south, west, east and centre).
Fig. Sampling after grinding
He considers critical parameters during
tableting to be the type of press, type of transport and transport rate of the bulk
product, pre-pressing, tableting speed, de-dusting and computerization. Parameters
analysed are tablet weight, thickness, friability, hardness, disintegration time and
In blister packing a possible adhesion of tablets and the
temperature and duration of sealing (possible degradation of the active substance) are
aspects relevant for validation. The ISPE baseline "Oral Solid Dosage Forms" may
be helpful in the qualification/validation of new production rooms.
As far as semi-solids are concerned, an expansion of the
qualification activities may need to be extended to the rooms (HVAC). Since the packaging
is an integral part of the product, particular attention should be paid to demixing during
Dr. Clemens RUFER, formerly of Schering AG, talked about "The
requirements for process validation in the active substance production sector". At
the beginning he explained the relevant bodies of regulations and pointed out that there
is currently no other GMP area in which so much change is taking place. Until now three
organizations (FDA, ICH, PIC/S) have compiled drafts on active substance GMP, all of which
also contain information on qualification/validation. As regards the necessary steps which
should be included in the validation Dr. Rufer showed a highly illustrative pyramid.
activities should start with the step (= critical step) from which influences on the
quality and purity of the finished product cannot be ruled out. Dr. Rufer quoted an old
Berlin saying to illustrate the term "critical": Critical is when if something
goes wrong the end doesn't go right either!
Dr. Rufer also provided examples of the structure of validation plans and reports at
Schering. He also pointed out the problems of retrospective validation which is receiving
less and less acceptance from the authorities. If, however, retrospective validation is to
take place, the mode of procedure must also be described in a validation plan. As regards
revalidations, Dr. Rufer said that they are necessary after process changes in
accordance with the changes and of course in the case of results indicative of a
process change (e.g. within the framework of the annual product review). This is why a
functioning change control system is very important. Along with SOP´s, the validation
documentation and the annual product reviews this is also frequently checked during
Dr. Rufer also spoke on the "Current state of the cleaning validation". He
began with an outline of the relevant bodies of regulations and pointed out that with the
revision of the PIC PH 1/96 paper its chapter on cleaning validation was also revised. Dr.
Rufer also considers an SOP or guideline to be necessary which describes the policy and
the execution of the cleaning validation in a company-specific form. It should contain the
- General principles (When cleaning validation is/is not necessary)
- General "Bracketing Concept"
- Description of the fundamental mode of procedure and the responsibilities
- Validation plans
- Sampling and test methods
- Selection and definition of limits
- Validation implementation
- Validation report
Procedure after completion of the validation (monitoring, review, revalidation)
Dr. Rufer paid special attention to several aspects:
When is validation of cleaning required? The requirement includes all steps in
pharmaceutical production and in active substance production at least from the "final
intermediate" state (possibly also earlier if residues might be carried on). In the
case of campaign production, cleaning is not necessary after every batch, but the cleaning
intervals should be defined (numbers of batches and times). For material which is
difficult to clean (e.g. filters) Dr. Rufer recommends "dedicated equipment".
The standing time between process end and cleaning or until renewed production should also
Social Event: Dr. Allgaier, Dr.
Verardi, Pat Jeater
the topic of "Bracketing" Dr. Rufer explained that identical product groups can
be combined to form product families if they are really comparable as regards their
chemicophysical properties (e.g. solubility). Identical equipment can be combined into
equipment families if they are comparable as regards their cleanability (e.g. surface,
material). As regards sampling technique (e.g. swabbing) Dr. Rufer urgently recommended
that recovery rates be determined.
Dr. Rufer sees the
0.1-% criterion, which is also given in the ICH Impurity Guideline, as a suitable cleaning
limit for active substances.
The changes to the chapter on cleaning validation resulting from the
new document PIC/S PR 1/99-1 were discussed in detail during the post-conference workshop.
Anthony J. TRILL, Senior Inspector of MCA, spoke on the GMP
requirements with respect to computerized systems. A. Trill sees the V-model as a general
condition for specification and testing.
|According to A. Trill,
attention is paid in inspections to whether the computerized system has a direct influence
on the safety and/or quality of the pharmaceutical product. Since computerized processes
and data records may also have a direct influence on product quality these are also
verified during the inspection.
The GMP regulations mention
only very general requirements as regards computerized systems and are therefore open to
interpretation, as A. Trill explained. In order to be in compliance, computerized systems
should be fully described, documented and their functions defined. They should also be
subject to quality-assuring measures, be validated and be in a controlled state.
Inspectors therefore pay attention to whether computerized systems are:
in the areas of R&D, manufacturing, quality control and along
the supply chain, that is up to distribution.
As well-known and useful bodies of regulations on compliance, A.
Trill recommends in addition to the GMP regulations in particular
GAMP 3 and the British document BS 7799.
|A. Trill lists the
following inspection topics:
- Non-compliance in supplier audits/QA and product certification
- Legacy system: retrospective validation and documentation of systems
- Project management and staff awareness training (QA staff and
- Year 2000 compliance
A. Trill complained that there is presently too little harmonization
as regards electronic signatures and reports. In the PIC/S an attempt is made to change
The last talk was by the moderator for the second day, Dr. Norman C.
FRANKLIN of Interactive Consulting GmbH i.G. Dr. Franklin began his talk with a historical
outline and the current requirements on the topic of changes and deviations, and explained
the differences between these two terms. After that he illustrated how the specifications
of the CFR can be applied to validation. How should one proceed in the case of deviations?
Basically there are four things to bear in mind when a deviation occurs:
- Determine that a deviation has occurred
- Examine the deviation
- Eliminate fault
- Repeat test
In case of a deviation in validation experiments in the laboratory
and in production a fault search should be initiated in order to determine whether
- a defective device
- an operating/processing error
- or other explainable fault
- was the cause. In these cases a repetition is allowed.
Dr. Franklin also mentioned the draft of the Guidance for Industry
on the topic of "Investigating out-of-specification (OOS) test results" which
reflects the FDA opinion on this topic.
Source: ECA Event European Validation
Conference and Post-Conference Workshop ,
5 - 7 May 1999, Berlin
Would you like more information? You can obtain the comprehensive
conference documents in English for DM 330.00 plus VAT and postage from CONCEPT
HEIDELBERG, Postfach 10 17 64, 69007 Heidelberg, Telephone 06221 / 84 44 0, Fax 06221 / 84
Author: S. Pommeranz, Project Manager, CONCEPT HEIDELBERG