55

Part 6: Qualification of cleanroom systems

6.1 Qualification - a powerful quality management tool

Qualification is a vital element for assuring and managing quality during the devel-
opment of an investment project, and an essential prerequisite to validation.

Systematic and documented qualification of premises, supporting utilities and pro-

duction equipment as well as systematic and documented validation of the produc-
tion processes are binding regulatory requirements in the life science industries
such as the pharmaceutical and medical device industries as well as pharmaceutical
biotechnology. Here, life and health of the product user may be at risk - and some-
times also the health of the personnel involved in the production operation, and of the
population in the vicinity of the manufacturing facility. In such situations, high formal
requirements for the relevant documentations are justified, e.g. hierarchically struc-
tured acceptance and signature requirements.

6.2 Qualification and validation - some definitions

Very precise definitions for the terms qualification and validation can be found (Fig.
6.03) in the recently published PIC/S guide for good practices for the preparation of
medicinal products in healthcare establishments [6.01], e.g. hospital pharmacies:
- Qualification is the risk based, systematic and documented action of proving that
facilities, rooms or equipment work correctly, are suitable for the intended pur-
pose and actually give the expected results;
- Validation is the risk based, systematic, GMP compliant and documented action
of proving that a defined process actually leads reproducibly to the required re-
sults.

There is a fundamental difference between qualification and validation (Fig. 6.04):

qualification is directed at premises, supporting utilities and process equipment,
whereas validation is process and product oriented. Supreme objective of both quali-
fication and validation is documented proof that the production process is capable of
manufacturing the product reliably and reproducibly in the specified quality.

Four qualification stages are distinguished (Figs. 6.05-6.06):

- Design qualification DQ is documented action of proving that premises, sup-
porting utilities and process equipment have been designed in compliance with
their design specification and in accordance with the adopted standards, guide-
lines and GMP requirements.
- Installation qualification IQ is documented action of proving that premises,
supporting utilities and the process equipment have been built and installed in
compliance with their design specification.
 56

- Operational qualification OQ is documented action of proving that premises,

supporting utilities and process equipment operate in accordance with their de-
sign specification.
- Performance qualification PQ is documented action of proving that premises,
supporting utilities and process equipment, as connected together, are capable of
producing the products reliably and reproducibly in accordance with the prede-
termined specification and quality attributes.

Qualification is an essential prerequisite for process validation: the final proof that
the process is capable of manufacturing the product or products reliably and repro-
ducibly with the specified quality. After successful process validation, the process is
ready and fit for manufacturing products for the market place.

The relationship between the qualification sequence and subsequent process valida-
tion is shown in Fig. 6.07. An important element merits introduction at this point in
time: change control, i.e. the systematic compilation of all changes having been
made to premises, supporting utilities and process equipment since freezing the de-
sign, and also of changes in manufacturing procedures and operational conditions
during later stages of the production system's life cycle (Fig. 6.08). In a first step,
such changes have to be assessed from the risk perspective: if they can be per-
ceived as potentially affecting the capability of the process to manufacture the prod-
ucts reliably and reproducibly in the specified quality, they will have to be submitted
to a full qualification cycle. Only by feeding back these changes into the qualification
sequence – thus keeping qualification up-to-date – the validation status of a produc-
tion system and its supporting utilities can be maintained uninterruptedly during its
entire life cycle.

6.3 Refocusing qualification objectives

GMP practices and, in this context, qualification and validation procedures, have as-
sumed quite a bad reputation over the years. GMP is frequently translated - not
completely without justification - into: "Give more paper". Driven by the pharmaceu-
tical inspection authorities, a most unhealthy trend developed over the years: to
qualify and validate what is capable of being qualified or validated – irrespective of
relevance from the product safety point of view. Thus, validation turned into an end
in itself, leading to enormous files of documents with an almost negligible information
density (Hiob [6.02]).

Fortunately the pharmaceutical regulatory authorities have reversed this trend re-
cently: FDA now promotes a risk based approach to inspections (Madsen [6.03]).
So do the Europeans: Annex 15 to the GMP guideline of the European Union and
PIC/S [6.04-6.05] determines that qualification and validation activities should be
based upon risk assessment and limit itself to those parameters which have been
identified as relevant process risks from the GMP point of view [6.02]. This new
approach has since been developed, as explained in Chapter 3.4, into a comprehen-
 57

sive pharmaceutical quality system of which quality risk management is an es-

sential element.

Viewed from the risk management angle, the objective of qualification and validation
is to prove domination of the critical aspects of a given production process and the
equipment and the utilities supporting it. The earlier practice of compiling an ever
increasing data quantity and infinite numbers of files is thus being reoriented into a
trend towards data relevance and file quality – quality thus substitutes quantity.

In parallel to qualification, and co-ordinated with it, technical acceptance tests for
all other functional aspects of the cleanroom system have to be performed according
to the established procedures of Good Engineering Practice, and documented
separately.

6.4 Optimizing the qualification efforts

6.4.1 Design qualification: a preventive approach

Regulatory authorities tend to focus upon the qualification stages subsequent to the
design phases of an investment object. This is understandable from the regulatory
authorities’ point of view and their focus upon process and product. The investor,
however, should perceive qualification also, and above all, as a potent tool for assur-
ing the technical quality and the economic potential of the investment to which he has
committed his money.

The fundament for a successful investment is laid during the design stage [6.06-
6.07], developed usually in three stages as shown in Chapter 4.1.

Unpleasant surprises at the IQ, OQ and PQ stages and during process validation
are, as a rule, the result of sloppiness and omissions during the design phase. The
objective of design qualification (Fig. 6.09) must therefore be to detect all design
weaknesses and omissions as early as possible during the design stage and well
before construction. Corrections are then - in these days of computer-aided design -
straightforward and inexpensive. Errors discovered during and after realisation, on
the other hand, are costly to correct, and frequently it is very difficult at that stage to
correct them satisfactorily.

A potent procedure for discovering design weaknesses, calculation errors and omis-
sions as early as possible during project development is to split Design Qualification
DQ into a sequence of three design qualification steps, each of which is performed at
the end of each project stage and comprehensively documented.

Following this approach, each design stage will end with a qualification exercise.
After its successful completion, the design is ready to proceed into the next develop-
ment stage. The objective of each of these qualification steps is (Fig. 6.10):
 58

- Design Qualification 1 (DQ 1): to assess the conceptual design for maturity to
be submitted to the go-ahead decision and subsequently to proceed into basic
design;
- Design Qualification 2 (DQ 2): to assess the maturity of the basic design as
prerequisite for the invitations for tendering to be emitted;
- Design Qualification 3 (DQ 3): to approve detail design, i.e. execution draw-
ings, material lists and material specifications as point of departure for the pur-
chasing decisions regarding the hardware for the building and installation phase.

This preventive approach, which is also recommended in the German guideline VDI
2083 Part 4.1 [6.08], will, in the end, save both time and money; also, full identifica-
tion of management with the project is assured at all times.

The definitions for the three design qualification stages are given in Fig. 6.11, and
Fig. 6.12 shows the relationship between them and the subsequent IQ, OQ and PQ
steps (from Erens [6.09]).

6.4.2 Change control: when to implement?

DQ 3 is, however, not yet the absolute end to design activities. Subsequent to DQ 3,
changes will still occur, possibly already during the installation phase if something
has been omitted, or if some requirements have changed. Such changes may also
happen later on during start-up, qualification and validation, in fact, during the entire
life cycle of the facility. As already stated in Chapter 6.2, the objective of change
control is to ensure maintenance of the qualification status forever.

The recommended kick-off date for the change control procedure to be activated is
the successful conclusion of the DQ 3 exercise, as by then changes should be the
exception rather than the rule.

6.5 Qualification Master Plans for contamination control systems

Validation Master Plans identify all qualification and validation activities to be per-
formed during design and realization of an investment object. It is good practice to
elaborate, as a sub-module of this plan, a specific Qualification Master Plan for the
contamination control system as the basic guideline for identifying all qualification
activities devoted to it. Determination of the measurement parameters to be incorpo-
rated into the qualification programme as opposed to the parameters that can be
handled through technical assessment procedures, is one of the most important fea-
tures of this plan. In compliance with Annex 15 - devoted to qualification and valida-
tion issues - of the GMP guideline of the European Community and PIC/S [6.04-
6.05], it is recommended to structure it as follows (Figs. 6.13-6.15):
- objective of the investment object and demarcation of its limits;
 59

- quality, qualification and process monitoring philosophies of the investor;

- protection objectives of the contamination control system;
- applicable regulatory compendia, standards, guidelines and company-internal
directives and procedures;
- definitions (if necessary);
- risk assessment of the manufacturing task as base for establishing the contami-
nation control objectives, for the determination of the scope of the qualification
services, and for the delimitation between qualification and acceptance tests;
- brief description of the contamination control system with emphasis upon its con-
tributions for enhancing process safety;
- outline of the qualification concept, the qualification time schedule and the qualifi-
cation responsibilities;
- identification of the qualification parameters and their acceptance limits;
- outline of the process monitoring concept and identification of the parameters to
be monitored complete with alarm and action limits, as well as of the requalifica-
tion concept;
- determination of the change control requirements and procedures;
- determination of the structure of the qualification files and assignment of the re-
sponsibility for file management;
- general requirements for the presentation of measurement data and test reports;
- list of attachments and appendices (if necessary).

If some of these topics had already been addressed in the Validation Master Plan,
they should be deleted from the compilation above and substituted by a reference to
said plan.

6.6 Qualification Plans and Qualification Reports

Based upon the Qualification Master Plan, detailed Qualification Plans are devel-
oped. They are established individually for each qualification stage; separate plans
are assembled for the building shell and for each of its infrastructure systems such as
the HVAC system.

The Qualification Report, again one each per qualification stage and separately for
the building shell and each individual infrastructure system, will list the results of all
checks and tests specified in the corresponding Qualification Plan, going into as
much detail as necessary, and finally summing up the results into a simple state-
ment: passed/not passed. Checks and tests requiring to be repeated should be
condensed into a list of pending actions. Only when all items listed therein have
 60

been addressed satisfactorily the qualification stage can be considered as con-

cluded.

Such Qualification Plans and the corresponding Qualification Reports are normally
structured identically, for instance as follows (Fig. 6.16):
- objective of the facility, its cleanroom system and the remaining utilities;
- short description of the system to be qualified;
- applicable regulatory guidance, normative and company-internal directives and
procedures;
- terms and abbreviations;
- signature lists, covering all people involved in the qualification activities covered
by this specific qualification plan and report;
- a detailed compilation of the required checks and tests, together with (where ap-
plicable) the measurement forms complete with acceptance criteria;
- calibration certificates (where applicable) of the measurement instrumentation;
- formal requirements for drawings and functional diagrams;
- allocation of responsibilities.

For realizing all checks and tests comprehensively, without missing anything, the
elaboration of a complete set of qualification checklists is very helpful. Extracts
from such checklists for DQ 2 and IQ are shown in Figs. 6.17-6.18. Comprehensive
sets of checklists for all qualification stages regarding the building and its HVAC sys-
tem are to be found in Appendix A3. The lists compiled there may be too detailed
for a small investment object, but not detailed enough for a complex case. Thus,
they should be adapted individually to the requirements of each individual investment
object.

Parameters for which technical acceptance tests are sufficient are not addressed in
these checklists.

6.7 Qualification and acceptance checks and tests

The ISO families of cleanroom technology standards provide a sound and compre-
hensive fundament for the qualification of cleanroom systems:
- ISO 14644-4 [6.10] devotes its Annex C to a very comprehensive compilation of
the requirements for the approval and qualification of cleanrooms. Fig. 6.19 pre-
sents the sequence of development, approval and qualification stages of an in-
vestment project and correlates them with the occupancy states of the clean
area. Annex C also contains a compilation of the many checks, tests and verifi-
cations to be performed during the different approval and qualification stages of a
facility.
 61

- ISO 14644-3 [6.11] offers detailed guidance for the measurement of physical pa-
rameters for qualification and acceptance tests as well as for process monitoring.
It addresses all such measurement tasks referred to in Parts 1 to 8 of the ISO
14644 series - a total of 13 tasks (Figs. 6.20-6.21). In addition, the minimum per-
formance requirements for the test instruments are specified in detail; an exam-
ple is given in Fig. 6.22.
- ISO 14698-1 [6.12] provides comprehensive guidance regarding microbiological
measurement procedures and ISO 14698-2 [6.13] regarding the assessment and
interpretation of biocontamination data.

A comprehensive requirement profile for test reports is to be found in Appendix A4.

6.8 Preparing for inspection

All stages of qualification have to be documented carefully, comprehensively and

transparently – following the stipulations determined in the Qualification Master Plan
and in the subsequent Qualification Plans and Reports. All safety relevant meas-
urements have to be performed with correctly calibrated instruments, and their
calibration certificates are an integral element of the qualification reports. Top
quality of this documentation has to be the aim: only complete, well-structured and
user-friendly documentations serve their quality assurance and process safety pur-
pose and will satisfy the inspection authorities. Inspectors do not perform tests and
measurements: their judgement of processes and the infrastructure serving them is
based almost exclusively on the documentations submitted to them. On the other
hand, competence of operators will be assessed on site through observation of their
conduct while performing their duties. Convincing files generate trust and are a pre-
requisite for inspection success. Weak and incomplete files, on the other hand, al-
most guarantee failure, and will lead to delays in approval and unnecessary costs for
correcting a situation which should never have been permitted to develop.

Some words regarding the regulatory authorities [6.14-6.15]: the inspectors ap-
pointed by them are public servants committed to ensuring that patients are supplied
with safe and effective medicinal products. If anything goes wrong, they will have to
bear their share of responsibility. Therefore, they are obliged to be critical, and to
inspect with a worst-case attitude based upon risk assessments. This critical attitude
should be viewed positively by industry: a lot can be learned from the inspectors'
comments and transformed into process improvements.

An idea regarding the aspects on which inspectors might focus when auditing phar-
maceutical infrastructure systems such as the HVAC system can be gleaned from
the PIC/S aide-mémoire on the inspection of utilities [6.16] which not only identifies
the key topics, but also crucial questions regarding them.

In order to avoid unpleasant surprises, it is advisable to consult the regulatory au-

thorities already in the early stages of the development of an investment project.
Some of them – and FDA is among these – urge you expressly to do so.
 62

6.9 References

[6.01] PIC/S PE 010-3: PIC/S guide to good practices for preparation of medicinal
products in healthcare establishments. Pharmaceutical Inspection Co-oper-
ation Scheme PIC/S, Pharmaceutical Inspection Convention PIC, Geneva
(1 October 2008).

[6.02] Hiob M.: Qualifizierung und Validierung nach Annex 15 des EG-GMP-Leit-
fadens - Teil 1: Allgemeine Anmerkungen aus Inspektorensicht (Qualification
and validation according to Annex 15 of the GMP guideline of the European
Union - Part 1: General remarks from an inspector's perspective). Pharm.
Ind. 63 (2001) 6, 563-570.

[6.03] Madsen R.E.: The quality systems approach to real compliance. Renhets-
teknik (Clean Technology) 36 (2007) 3, 10-15..

[6.04] 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).

[6.05] 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).

[6.06] MacDonald A.: Do you DQ? Design qualification challenges and considera-
tions. Pharmaceutical Engineering 25 (2005) 2, 30-38.

[6.07] Chvaicer Y.: Design qualification in practice - from strategy to report. Phar-
maceutical Engineering 25 (2005) 4, 92-104.

[6.08] VDI 2083: Cleanroom technology - Part 4.1: Planning, construction and
start-up of cleanrooms. Beuth Verlag, Berlin (October 2006).

[6.09] Erens St.: Qualifizierung von Lüftungsanlagen und Reinräumen (Qualification

of HVAC systems and cleanrooms). Pharm. Ind. 69 (2007) 9, 1081-1086.

[6.10] ISO 14644-4: Cleanrooms and associated controlled environments - Part 4:

Design, construction and start-up. International Organization for Standard-
ization ISO, Geneva (April 2001).

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

Test methods. Ibid. (December 2005).
 63

[6.12] ISO 14698-1: Cleanrooms and associated controlled environments - Biocon-

tamination control - Part 1: General principles and methods. Ibid. (Septem-
ber 2003).

[6.13] ISO 14698-2: Cleanrooms and associated controlled environments - Biocon-

tamination control - Part 2: Evaluation and interpretation of biocontamination
data. Ibid. (September 2003).

[6.14] Hiob M.: Inspektionen (Inspections). Pharm. Ind. 68 (2006) 9, 1101-1102.

[6.15] Fetsch J., Mocha Denise: Vorbereitung und Begleitung von FDA-Inspektio-
nen (Preparation and accompaniment of FDA inspections). Pharm. Ind. 67
(2005) 4, 455-461.

[6.16] PIC/S PI 009-3: Aide-mémoire on inspection of utilities. Pharmaceutical In-

spection Co-operation Scheme PIC/S, Pharmaceutical Inspection Convention
PIC, Geneva (14 September 2007).