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Part 7: Monitoring and requalification

7.1 Objectives of process monitoring

Many pharmaceutical production tasks - especially if microbiological risks are to be

dominated - require proof that the stipulated air cleanliness levels and other contami-
nation control parameters have been met continuously and consistently during pro-
duction.

This is but one of the many tasks of process monitoring, a task encompassing all
measurement and documentation activities around the manufacturing process. The
objective is to obtain a comprehensive set of data in order to prove that the process
has operated uninterruptedly within the specified limits. The contamination control
related parameters are a fully integrated element within this general context of proc-
ess monitoring.

Key contamination control data are, especially for sterile processing, an indispensa-
ble element of the batch documentation. On the other hand, they are just as indis-
pensable for the automatic control of the air circulation system. Thus, they have to
be fed, on the one hand, into the building control system, and on the other hand, in-
corporated into the process monitoring system.

7.2 Data management stipulations

As integral part of the batch documentation, the key contamination control data are
an essential element of the quality assurance system serving both product and pro-
duction. Data collection of the physical measurement parameters is, as a rule, per-
formed automatically by means of computerized systems. As such, they have to sat-
isfy comprehensive regulatory requirements which are laid down in Annex 11 to the
GMP guideline of the European Community and PIC/S [7.01-7.02] and, in the context
of FDA regulations, in 21 CFR 11 [7.03]. The computerized systems addressed in
these guidance documents require validation and this should be performed according
to the GAMP 5 (GAMP = Good Automated Manufacturing Practices) specifications
[7.04], which have recently substituted the earlier GAMP 4 guide [7.05]. Data secu-
rity must be ensured above all over a long period of time: general legislative re-
quirements for the minimum record keeping period have to be met, and data must
remain accessible for a time interval well beyond the expiry date of the product batch
to which they refer. The data management system must also ensure safeguarding
the data against access to them by unauthorized persons and against falsification.
The main safety criteria to be corroborated through validation are compiled in Fig.
7.03.

Building control systems with their extensive ramifications throughout the entire build-
ing complex of a site, of which the manufacturing facilities are normally but one of
many elements, are not capable of being validated. Therefore, it is imperative that
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data management for process monitoring purposes is completely independent from

the building control system and cannot be manipulated through it. Persons author-
ized for interference into the building control system will, as a rule, not have access
to the process monitoring system.

7.3 Process monitoring of pharmaceutical cleanroom systems

Pharmaceutical cleanroom systems will, as a rule, require monitoring both of physical

and of microbiological parameters. Instrumentation employed for monitoring critical
parameters requires periodical recalibration which must be corroborated through
valid calibration certificates. In most cases, the stipulated interval between recalibra-
tions is one year.

7.3.1 Physical parameters

The most important physical contamination control parameters to be measured and

recorded within the general coverage of process monitoring are particle concentra-
tions and pressure differences between rooms; another important parameter fre-
quently incorporated into the monitoring concept is the air velocity (in the case of
unidirectional airflow) or the air flow rate (in the case of turbulent airflow) (Fig. 7.04).
In clean areas with exacting contamination control requirements these parameters
should, if possible, be measured continuously, or at least frequently, i.e. updated
at specified intervals not exceeding 60 min during operation [7.06].

Monitoring of physical parameters of this kind provides instant answers, and they
are therefore ideally suited for process control and supervision purposes. They pro-
vide, however, only an indirect and incomplete answer if microbiological process
risks are to be assessed.

7.3.2 Microbiological parameters

For assessing the microbiological risks eventually incurred during the manufacture of
sterile products, monitoring of physical parameters will have to be complemented by
direct microbiological tests, albeit at a reduced frequency of sampling in compari-
son with the physical parameters.

What microbiological limits will have to be met? The microbiological tests required by
FDA for aseptic processing [7.07] had been summarized in Chapter 2.8 and Fig.
2.34; the somewhat more comprehensive list of parameters and the corresponding
limits to be found in Annex 1 of the GMP guideline of the European Union and PIC/S
are reproduced in Fig. 7.05. The drawback of the present microbiological methods,
i.e. the long delay until availability of the results, will have to be accepted as a neces-
sary evil for the time being. Hopefully, rapid detection methods may come close to
practicality soon (see Chapter 1.5).
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Sampling of airborne micro-organisms can be remotely controlled. All other microbi-

ological assessment techniques require interference into critical processing areas
through manual sampling, using procedures which, strictly speaking, cannot be clas-
sified as sterile. As a consequence, such sampling procedures have to be ranked as
process risks! This problem merits attention above all in the context of the new ad-
vanced processing technologies with enhanced sterility assurance level, i.e. blow-fill-
seal, RABS and isolator technology.

The topic of microbiological sampling as a process risk is only addressed summarily

in Annex 1 of the GMP guideline of the European Community and PIC/S ([7.01-7.02],
Annex 1, item 18), with the brief statement that sampling methods used in operation
should not interfere with zone protection; a similar brief statement can be found in
the PIC/S recommendations on validation of aseptic processes [7.08]).

This issue is addressed more extensively in the monography <1116> of the U.S.
Pharmacopeia [7.09]. Here, it is recommended to balance the frequency of environ-
mental microbiological sampling with the benefits accrued by the results of such
monitoring. Once qualification and validation have established the effectiveness of
the protection concept in controlling the microbiological risks, then a comparatively
low frequency of sampling for routine monitoring of the microbiological status of the
processing area can be adopted, which must, however, under all circumstances meet
the batch documentation requirements. This shift of microbiological assessment
from monitoring to the prior qualification and validation activities is another argument
in favour of comprehensive qualification and validation efforts.

7.4 Alarm and action limits

During the operation of the cleanroom system, unpleasant surprises are to be

avoided as far as possible. In order to ensure early warning against any problems
cropping up, alarm and action limits should be established for the key parameters
to be monitored. They also provide a sound and objective fundament for trend
analyses of process and cleanroom performance. The following definitions apply
(Fig. 7.06):
- Alarm limit: a predetermined value somewhat outside the normally expected
range. If exceeded, intensified supervision should be triggered according to a
pre-determined plan in order to ensure that the process and/or the environment
remain under control.
- Action limit: a predetermined value substantially outside the normal range. If
exceeded, immediate formal action according to a predetermined plan specifying
the necessary investigative and corrective actions is to be triggered.

A practical procedure for determining alarm and action limits is given in [7.10].
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7.5 Operation and maintenance

Cleanroom systems should run continuously. In facilities with single-shift utilization,

the reduction of the air flow rate outside production hours, i.e. in the occupancy state
at rest, is a potent energy cost saver: a reduction of the air flow rate to 50 % of the
nominal value will reduce energy costs by more than 80 %! Of course, the predeter-
mined pressure differences between rooms as well as the predetermined air flow pat-
tern must be maintained uninterruptedly during system operation with reduced air
flow rate.

Valuable advice regarding the operation of cleanroom systems and the principal risks
to be addressed can be found in ISO 14644-5 [7.11] and in the German guideline
VDI 2083 Part 5.1 [7.12] covering this topic in particularly exhaustive detail.

Maintenance of the HVAC system of a clean facility follows, in general terms, the
procedures employed for other industrial air-conditioning systems. The only peculiar-
ity is HEPA filtration: the pressure difference between the upstream and the down-
stream filter faces requires periodical assessment (two or four times a year), which is
performed and recorded manually. When the predetermined maximum pressure dif-
ference is reached, the filter needs to be replaced. After the filter change, an in-
stalled filter leak test according to ISO 14644-3 [7.13] is recommended, as part of the
extraordinary requalification of the cleanroom system then to be performed (see
Chapter 7.6 hereafter).

7.6 Requalification

The requalification of cleanrooms is covered in ISO 14644-2 [7.06]. The principal

objective is to prove continued compliance with the air cleanliness classes according
to ISO 14644-1 stipulated for the installation. Two situations are distinguished:
- periodical requalification at intervals depending on the air cleanliness classifi-
cation of the cleanroom, as specified in ISO 14644-2;
- extraordinary requalification after the events compiled in Fig. 7.07.

Cleanroom requalification should address, according to ISO 14644-2, at least the

following parameters (Fig. 7.08):
- verification of the air cleanliness class;
- verification of pressure differences between rooms;
- verification of the air velocity (for unidirectional airflow) or of the air flow rate (for
turbulent airflow).

ISO 14644-2 also gives recommendations for non-normative additional tests, to be

included into the testing plan if deemed appropriate. For aseptic processing, FDA
expects the installed filter leak test to be performed at least twice a year [7.07].
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Requalification of a cleanroom system normally addresses only the physical meas-

urement parameters, and is performed in the at rest occupancy state. Some opera-
tors of facilities for aseptic manufacturing extend requalification also to the microbial
limits which must, of course, be assessed in the occupancy state in operation. Such
microbiological requalifications normally incorporate a trend analysis covering the
time interval since the last requalification of this kind, with special attention to any
untoward events recorded in this period and assessment of the success of the ac-
tions taken subsequently to said events. Such periodical trend analyses are also
recommended for the risk-relevant physical monitoring data.

The interval between periodical requalifications is normally one year - possibly less if
high levels of air cleanliness (ISO Class 5 in the occupancy state in operation or bet-
ter) have to be maintained. However, if the cleanroom system is equipped with in-
strumentation for continuous or frequent monitoring this interval may be extended,
provided that the results of the continuous or frequent monitoring remain within the
specified limits [7.06].

7.7 Summing up….

Here ends this workshop, and it seems appropriate to terminate with the famous
statement of Konrad Lorenz (Fig. 7.09, from [7.14]):
- listening does not guarantee understanding;
- understanding does not guarantee acceptance;
- acceptance does not guarantee application;
- application does not guarantee long-term adherence.

Hopefully, the many exercises have at least helped understanding….

In this workshop, the speaker's objective has been to address cleanroom and con-
tamination control technology from a multitude of angles, with special attention to risk
and to risk management issues. All elements must interact harmoniously, as a chain
is only as strong as its weakest link. Contamination control is synonymous with an
open mind, a risk-addressing mentality and an integral, all-embracing approach:
that's the appropriate spirit - may it guide you forever in your contamination control
activities.

7.8 References

[7.01] Eudralex, the rules governing medicinal products in the European Union - Vol.
4: EU guidelines to Good Manufacturing Practice for medicinal products for
human and veterinary use. European Commission, Brussels (frequently up-
dated).
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[7.02] PIC/S PE 009-9: Guide to Good Manufacturing Practice for medicinal prod-
ucts (divided into four parts: Introduction, Part I, Part II, Annexes). Pharma-
ceutical Inspection Convention PIC, Pharmaceutical Inspection Co-operation
Scheme PIC/S, Geneva (1 September 2009).

[7.03] 21 CFR 11: Guidance for industry - Electronic records; electronic signatures
- Scope and application. U.S. Department of Health and Human Services,
Food and Drug Administration, Rockville MD/USA (August 2003).

[7.04] GAMP 5: A risk-based approach to compliant GxP computerized systems.

ISPE - The International Society for Pharmaceutical Engineers - in collabora-
tion with FDA and other regulatory authorities. Tampa FL/USA (2008).

[7.05] GAMP 4: The Good Automated Practice (GAMP) guide for validation of
automated systems in pharmaceutical manufacture. ISPE - The International
Society for Pharmaceutical Engineers - in collaboration with FDA. Ibid. (De-
cember 2001).

[7.06] ISO 14644-2: Cleanrooms and associated controlled environments - Part 2:

Specifications for testing and monitoring to prove continued compliance with
ISO 14644-1. International Organization for Standardization ISO, Geneva
(September 2000; presently in revision).

[7.07] Guidance for industry: Sterile drug products produced by aseptic processing
- current Good Manufacturing Practice. U.S. Department of Health and Hu-
man Services, Food and Drug Administration, Rockville MD/USA (September
2004).

[7.08] PIC/S PI 007-5: Validation of aseptic processes. Pharmaceutical Inspection

Co-operation Scheme PIC/S, Pharmaceutical Inspection Convention PIC,
Geneva (25 June 2009).

[7.09] USP Informational Chapter <1116>: Microbiological evaluation of clean

rooms and other controlled environments. U.S. Pharmacopeia, Eighth Sup-
plement, USP 31 (2008), p. 582-589 (presently in revision).

[7.10] Agalloco J.: Qualification and validation of environmental control systems.

PDA Journal of Pharmaceutical Science & Technology 50 (1996) 5, 280-289.

[7.11] ISO 14644-5: Cleanrooms and associated controlled environments - Part 5:

Operations. International Organization for Standardization ISO, Geneva (Au-
gust 2004).

[7.12] VDI 2083: Cleanroom technology - Part 5.1: Cleanroom operation. Beuth
Verlag, Berlin (September 2007).

[7.13] ISO 14644-3: Cleanrooms and associated controlled environments - Part 3:

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Test methods. International Organization for Standardization ISO, Geneva

(December 2005).

[7.14] Nieth K.F.: Reinraumgerechtes Mitarbeiterverhalten (Cleanroom compatible

behaviour of staff). Reinraumtechnik 6 (1992) 6, 34-37.