Outs 041 Schicht

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Dr Hans H Schicht is Executive

Secretary of the Swiss Society for

Contamination Control (SRRT) and

represents Switzerland on the

International Organization for

Standardization (ISO) and the

European Committee for

Standardization (CEN) Technical

Committees for standardisation in

the field of clean room technology.

He is an independent consultant

specialising on clean room

technology and contamination

control, with more than 30 years

of experience in this field.

a report by

Dr H an s H S c h i c h t

Executive Secretary, Swiss Society for Contamination Control (SRRT)

New Regu l a to r y Gu i dan c e

Pub l i s h ed i n Eu rope and th e U S

In recent months, new regulatory guidance for the

manufacture of sterile medicinal products was

published on both sides of the Atlantic:

In August 2003, the US Food and Drug

Administration (FDA) published a second draft of

a revised guidance document on sterile drug

products produced by aseptic processing.1

In September 2003, a revised edition of Annex 1

devoted to the manufacture of sterile medicinal

products to the Good Manufacturing Practice

(GMP) guideline of the European Community

(EC) entered into force.2

The FDA draft is a revision of a preliminary conceptpaper published in September 20023 as a first step

towards replacing the 1987 Industry Guideline on

sterile drug products produced by aseptic processing.4

It describes the FDAs current thinking and contains

recommendations on how current Good

Manufacturing Practice (cGMP) regulatory

requirements as stipulated in the Code of Federal

Regulations (CFR), Sections 210 and 211 should

be interpreted by industry.

The revised Annex 1 replaces previous wording, which

came into effect on 1 January 1997. It is an integral partof the GMP guideline of the EC for the manufacture

of medicinal products and provides specific regulatory

guidance for the manufacture of sterile medicinal

products. It covers terminally sterilised products as well

as products manufactured aseptically.

Both regulatory guidance documents make reference

to the International Organization for Standardization

(ISO) series of clean room technology standards.

Indeed, they rely on them for implementing theregulatory requirements regarding design, construc-

tion, qualification and monitoring of contamination

control systems.

Th e I SO and Eu ropean Commi t t e e f o r

S t anda rd i z a t i o n S e r i e s o f C l e an Room

S tanda rd s

Since 1990, the ISO and The European Committee

for Standardization (CEN) have been jointly

developing two families of contamination control

standards:5

the European Standard (EN) ISO 14644 series on

clean room technology in general; and

the EN ISO 14698 series on biocontamination

control.

A compilation of the standards already issued and under

development is presented in Table 1. The column

status 12-03 in this table identifies the actual state of

approval for each work item, the approval procedure

being subdivided into the following three stages:

an informal circulation as a Committee Draft,

with the objective of inviting technical comments

Regula tory Guidance for Manufac tur ing Ste r i l e Pharmaceut i ca l Products

Recen t EC and FDA Deve lopments

1

Reference Section

B U S I N E S S B R I E F I N G : P H A R M A O U T S O U R C I N G

1. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice,

US Department of Health and Human Services, US Food and Drug Administration (FDA) (draft guidance for comment

purposes only not for implementation, 22 August 2003).

2. Ad Hoc GMP Inspections Services Group: EC Guide to Good Manufacturing Practice Revision to Annex 1:

Manufacture of Sterile Medicinal Products, European Commission, Brussels, 30 May 2003.

3. Sterile Drug Products Produced by Aseptic Processing, draft, US Department of Health and Human Services, US Food

and Drug Administration (FDA), Rockville, Maryland, USA (preliminary concept paper not for implementation, 27

September 2002).4. Guideline on Sterile Drug Products Produced by Aseptic Processing, US Department of Health and Human Services,

US Food and Drug Administration (FDA), Rockville, Maryland, USA, June 1987, reprinted June 1991.

5. H H Schicht, The ISO Contamination Control Standards A Tool for Implementing Regulatory Requirements,

European Journal of Parenteral & Pharmaceutical Sciences, 8 (2003) 2, pp. 3742.


2/5B U S I N E S S B R I E F I N G : P H A R M A O U T S O U R C I N G

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Reference Section

from the nations actively involved in the

development of the standard;

a first formal circulation as Draft International

Standard (DIS) for the parallel ISO and CEN

enquiries, inviting technical and editorial comments

and requesting a generic statement on the merits of

the draft by means of a preliminary vote; and

the second formal circulation as Final Draft

International Standard (FDIS), for the parallel ISO

and CEN voting leading if successful to

approval and subsequent publication in the ISO

and CEN collections of standards.

As soon as a standard has been circulated as a DIS, it

can be purchased through the national standardisation

bodies. From this instant, it may be utilised as a base

document for job specifications and contracts and it is

considered as state of the art in any legal dispute. With

five clean room standards formally approved and

another four at DIS level, comprehensive guidance is

currently available in this field for serving industry.

The point of departure of this standardisation effort is

the air cleanliness classification scheme according toEN ISO 14644-1.6 It is distinguished by a

mathematically coherent approach and based on the

following formula:

Cn = 10N(0,1/D)2,08

where Cn = maximum number concentration of

particles per cubic metre (m3) with a diameter the

considered particle diameter, rounded to a maximum

of three digits; N = ISO classification number; D =

considered particle diameter; and 0,1 = the reference

diameter, a constant with the dimension m.

Table 2 presents the ISO class limits in tabular form.

Th e N ew Ed i t i o n o f A nn ex 1 t o t h e

EC GMP Gu i de l i n e

The precipitated formal adoption of the revised

Annex 1 to the GMP guideline of the EC was an

unpleasant surprise for many in the industry. After

all, the draft had only been released for public

consultation in November 2002. A mere five months

later, the ad hoc GMP inspectors group responsible

for the revision prepared the final draft for the

subsequent formal adoption by the Pharmaceutical

Committee of The European Agency for theEvaluation of Medicinal Products (EMEA). The

6. EN ISO 14644-1: Cleanrooms and Associated Controlled Environments Part 1: Classification of Air Cleanliness, May

1999.

Table 1: The EN ISO Series of Clean Room Standards and their Status of Development

Document no. Short title Status 12-03

ISO 14644-1 Air cleanliness classification Std 05-99

ISO 14644-2 Testing cleanrooms for continued compliance with ISO 14644-1 Std 09-00

ISO 14644-3 Metrology and test methods DIS 09-02

ISO 14644-4 Design, construction and start-up Std 04-01

ISO 14644-5 Operation DIS 07-01

ISO 14644-6 Terms and definitions CD 06-01

ISO 14644-7 Mini-environments, glove boxes, isolators DIS 02-01

ISO 14644-8 Classification of airborne molecular contamination CD 12-02

ISO 14698-1 Biocontamination control General principles and methods Std 09-03

ISO 14698-2 Biocontamination control Evaluation and interpretation of biocontamination data Std 09-03

ISO 14698-3 Biocontamination control Measuring the efficiency of cleaning and disinfection DIS 02-99

processes of inert surfaces

Table 2: The Air Cleanliness Class Limits According to ISO 14644-1

ISO Classification Maximum concentration limits (particles/m3 of air) for

No. particles of the considered sizes shown below

0.1m

0.2m

0.3m

0.5m

1m

5mISO Class 1 10 2

ISO Class 2 10024 10 4

ISO Class 3 1,000237 102 35 8

ISO Class 4 10,0002,370 1,020 352 83

ISO Class 5 100,00023,700 10,200 3,520 832 29

ISO Class 6 1,000,000237,000 102,000 35,200 8,320 293

ISO Class 7 352,000 83,200 2,930

ISO Class 8 3,520,000 832,000 29,300

ISO Class 9 35,200,000 8,320,000 293,000


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Regulatory Guidance for Manufac tur ing Ster i le Pharmaceut ica l Products

many suggestions submitted by renowned bodies of

the pharmaceutical industry were given no serious

consideration;710 the text finally adopted is almost

identical in its wording to the previous draft.

The principal and most controversial changes in

comparison with the previous edition concern the

determinations for particles of 5m diameter andabove as well as the corresponding ones for the

recommended sample volume of air.

The particle concentration limits according to the

revised Annex 1 for the room Grades A to D are

provided in Table 3. Those for particles of 0.5m

diameter and above are unchanged in comparison to

the previous edition, whereas the concentration limit

for particles of 5m diameter and above has been

changed, for the Grade A areas and for Grade B at

rest, from zero to one particle 5m diameter per

m3

of air. Mathematically, this is a step in the rightdirection; but proving a concentration value as low

as one particle per m3 with statistical confidence by

means of discrete-particle counters with their airflow

rate of not more than one cubic foot per minute

equal to 28.3 litres per minute is simply not feasible.

For particles of 0.5m diameter and above, the limit

values for room Grade A and for room Grade B at

rest correspond with the ISO Class 5. As Table 2

shows, the corresponding ISO Class 5 limit value for

particles 5m is 29 particles per m3, a limit capable

of being verified straightforwardly with statisticalassurance. It came as a disappointment to many

professionals that the European regulatory authorities

have refrained from adopting the internationally

recognised ISO 14644-1 air cleanliness classes also for

the particles of 5m and above. No science-based

explanations have been given so far by the European

regulators for the reasons behind this decision.

The recommended sample volume of 1m3 of air for

Grade A and B areas and preferably also for Grade C

areas is another new requirement raising a number

of questions. Again, no science-based justification is

offered for this determination. How is this

requirement to be interpreted in practice? Is this the

sum of the individual air samples taken in a work area

or is this requirement to be met individually for each

sampling location? If it applies to each sampling

location, do the inspectors expect a continuousmeasurement, with a printout of the result only after a

total air throughput of 1m3 through the discrete-

particle counter, i.e. after a counting period of 36

minutes? Such an extended sampling period would

neutralise the most welcome capability of the discrete-

particle counter: to provide instant data regarding

unacceptable deviations of the particle status from the

desired range to which operators could react without

delay. If the 1m3 could be interpreted as the sum of 36

samplings of one minutes duration each, this instant

information would not be lost. Some inspectors seem

to accept this summing up but is it safe to assumethat this is a generally acceptable procedure?

Another unfortunate determination is the requirement

regarding the airflow pattern in the critical areas of

high-risk operations, such as the filling and closing

zone during aseptic filling of ampoules, phials and

syringes. Annex 1 requires protection of such high-risk

areas by laminar airflow systems, which should

provide an homogeneous air velocity in the range of

0.360.54 metres per second (m/s) at the working

position. Two objections must be raised here.

The first concerns the term laminar airflow.

Laminar airflow, correctly speaking, is an aero-

dynamic term signifying an airflow pattern devoid of

any turbulence. Under clean room conditions, such

a flow pattern is inherently unstable and cannot be

maintained in a pharmaceutical filling and closing

area. Using this term in the clean room technology

context is a relic from the past it had been used

clumsily and carelessly for many years for describing

a low-turbulence airflow pattern where the air

7. S Fairchild, May 2003 Revision of the Annex 1 to the EU GMP Guide, GMP Review, 2 (2003) 3, pp. 57.8. J Sharp, Letter to the Editor: Annex 1, ibid., pp. 45.

9. M Finke and H Schulz, Aktuelles zu GMP-Regularien (GMP Regulatory Documents: Current Issues), Pharm. Ind.,

65 (2003) 10, pp. 1,0651,069.

10. H H Schicht, The Revised Annex 1 to the EC GMP Guideline, GMP Review, 2 (2003) 3, pp. 711.

Table 3: Room Grades for the Manufacture of Sterile Medicinal Products According to Annex 1 (September

2003) of the EC GMP Guideline

At rest (b) In operation

Room grade Maximum permitted number of particles/m3 equal to or above (a)

0.5m (d) 5m 0.5m (d) 5m

A 3,500 1 (e) 3,500 1 (e)

B (c) 3,500 1 (e) 350,000 2,000

C (c) 350,000 2,000 3,500,000 20,000

D (c) 3,500,000 20,000 not defined (f) not defined (f)

Notes af: please refer to Annex 1 directly.

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Reference Section

moves on more or less parallel streamlines. In the

standards literature and above all in the EN ISO

standards on clean room technology, it has been

replaced systematically with the scientifically correct

terms unidirectional airflow or low-turbulence

displacement airflow. Should GMP guidance not be

expected to employ scientifically correct wording

where this has become generally accepted?

The second objection refers to the arbitrary fixing

of numerical air velocity limits. Again, the GMP

authorities owe a science-based justification for this

requirement. No corresponding determinations are

to be found in the EN ISO clean room standards

and in the next-generation FDA guidance for

aseptic manufacturing.

These are just a few examples of weaknesses in the

revised Annex 1. It is hoped that this unfortunate

document will be withdrawn soon and replaced

by determinations expressed in precise andscientifically sound wording, during the develop-

ment of which competent suggestions by industrys

professional bodies will be submitted to a fair,

science-based assessment.

Th e N ew FDA D ra f t Gu i de l i n e

A n O ve r v i ew

Since the publication of the FDA guideline on

aseptic processing of pharmaceutical drugs in 1987,4

pharmaceutical technology and contamination

control, as well as the corresponding technicalstandards, have made considerable progress.

In September 2002, a first draft of the long-expected,

completely revised guidance document on aseptic

processing was published as a preliminary concept

paper not for implementation. Unfortunately,

many of the determinations still reflected the earlier

guideline and left a lot to be desired. Accordingly,

many recommendations for improvement were

submitted by industry (e.g. that by R Madsen11).

In the second draft, published in August 2003, again

intended for comment purposes only not for

implementation many of these suggestions had been

adopted into the text. With 2,059 lines on 59 pages, it

can be considered an excellent and most compre-

hensive point of departure for the final editing process.

Table 4 shows the list of contents of this draft; it also

illustrates how much of the total text is devoted to

each section. Each section begins with a listing of the

applicable paragraphs of the cGMP regulations (CFR

Sections 210 and 211) and is followed by detaileddescriptions of what FDA currently expects from

industry in order to comply with these rules. It

focuses on the cGMP issues of finished drug

products. Some basic determinations regarding the

processing steps prior to the filling and sealing

operations are addressed in Appendix 3.

The air cleanliness classification scheme for work

areas involved in aseptic processing is provided in

Table 5. Particle concentration limits are established

for particles 0.5m only and they are based strictly

on and refer to EN ISO 14644-1. The identificationof the air cleanliness classes, however, follows the

Table 4: FDA Draft Guidance for Aseptic Processing (August 2003 Table of Contents)

I. Introduction 2.5%

II. Background 2.3%

III. Scope 1.0%

IV. Buildings and facilities 14.4%

V. Personnel (training, qualification and monitoring) 5.5%

VI. Components and container/closures 5.6%

VII. Endotoxin control 1.3%

VIII. Time limitations 0.8%

IX. Validation of aseptic processing and sterilization 21.7%

X. Laboratory controls 9.9%

XI. Ster ilit y testing 7.8%

XII. Batch record review: Process control documentat ion 1.6%

Appendix 1: Asept ic processing isolators 8.9%

Appendix 2: Blow fill seal technology 4.6%

Appendix 3: Processing prior to fill ing and sealing operat ion 3.0%

References 1.0%Relevant guidance document 0.9%

Glossary 6.4%

11. R Madsen, PDA Comments on the FDA Preliminary Concept Paper Sterile Drug Products Produced by Aseptic

Processing, PDA Letter, 38 (2002) 11, pp. 1, 1115.



traditional American practice, with the cubic feet as

volume unit (as an example, Class 100 = 100

particles

0.5m per cubic foot at class limit = 3,520particles 0.5m/m3 at class limit = ISO Class 5). All

classification indications refer to the occupancy state

in operation; no determinations whatsoever are made

for the at-rest occupancy state.

Two kinds of classified areas are distinguished:

critical areas Class 100 (ISO 5); and

supporting clean areas, classified as depending

upon the contamination risk either Class 10,000

(ISO 7) or Class 100,000 (ISO 8).

There is no direct equivalent to the European room

Grade D.

With regard to airflow patterns, unfortunately both

the terms unidirectional airflow and laminar

airflow are used in the text and, as such, rather

indiscriminately. This practice is not quite coherent

with the correct definition for both terms given in the

glossary of the draft. However, it is encouraging to

read the flow pattern requirements for points of

critical exposure: laminar flow should be maintainedat a velocity sufficient to sweep particles away from

the filling/closing area and maintain unidirectional

airflow during operations. This wording establishes

clearly the objective that the airflow pattern is

expected to achieve an excellent substitution for the

earlier velocity requirement of 0.45m/s 20 % still

being upheld by the European regulatory authorities.

An exhaustive appendix is devoted to isolator tech-

nology. This is the first time for FDA to pronounce

itself officially on this important new technology for

the protection of aseptic filling operations.

In summation, the FDA Draft Guidance is an

impressive document clarifying the FDA position in

detail maybe in too much detail. The frequent useof the wording an accepted procedure is is prone

to be interpreted in a narrow way as the specific

procedure FDA wants to see. This may place

equivalent procedures, which have not been

specifically mentioned, at a disadvantage, with the

risk of impeding progress.

I n t e rn a t i on a l H a rmon i s a t i o n o f

GMP Gu i dan c e

Comparing the attitudes behind the new regulatory

documents for sterile manufacturing, differentphilosophies seem to be followed on both sides of the

Atlantic. The apparent openness to dialogue with

industry so apparent in recent FDA policy and in the

new-generation FDA guidance documents is not yet

reflected by the European regulators. Even worse,

the European and American GMP requirements for

aseptic processing and the manufacture of sterile

medicinal products seem to drift apart more and

more. If both authorities have to be satisfied and

this, nowadays, is the normal situation extra effort

and as a consequence extra cost is incurred.

Therefore, international harmonisation of GMPguidance documents would be a most desirable goal

for the years to come.

A suitable body for handling such a task already is in

existence the International Conference on

Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use

(ICH), a tripartite joint conference embracing the

regulatory authorities of the EU, the US and Japan.

This body has already established, with its GMP

determinations for active pharmaceutical ingredients,12

a track record of handling such tasks competently.

Regulatory Guidance for Manufac tur ing Ster i le Pharmaceut ica l Products

12.ICH Harmonised Tripartite Guideline ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients,

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use,

November 2000, adopted as Annex 18 into the GMP Guideline of the European Community.

Table 5: FDA Draft Guidance for Aseptic Processing (August 2003)

Buildings and facilities Air classificationsa

Clean area ISO designationb Particles Microbiological Microbiological

classification 0.5m/m3 active air action settle plates

(particles 0.5m) levelsc (cfu/m3) (90mm diameter)

action levelsc,d

(cfu/4 hours)

100 ISO Class 5 3,520 1e 1e

1,000 ISO Class 6 35,200 7 3

10,000 ISO Class 7 352,000 10 5

100,000 ISO Class 8 3,520,000 100 50

Key: a = all classifications based on data measured in the vicinity of exposed materials/articles during periods of activity; b= ISO 14644-1 designations provide uniform

particle concentration values for clean rooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A; c= values

that represent recommended levels of environmental quality. It may be appropriate to establish alternate microbiological levels due to the nature of the operation.

d = the additional use of settling plates is optional; e = samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

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