gmp trends: contamination control according to … · gmp trends: contamination control according...

ETIF 2008Costa Salguero

Centre -

Buenos Aires -

Argentina

24 October 2008

Giovanni Bini

“Revision of Annex 1, 14/02/2008”

GMP Trends:

Contamination control according to Annex I effective from 2009

2

Contents

Revision History

Introduction

Cleanrooms Classification

Cleanrooms Routine Monitoring

Blow/fill/seal

Media Fill

Bioburden

Capping of vials

Conclusions

3

EU GMP –

Annex 1 –

Manufacture of Sterile Medicinal Products

Revision September 2003

EU GMP –

Annex 1 –

Manufacture of Sterile Medicinal Products (1997)

Revision Annex 1Revisions History

EU GMP –

Annex 1 –

Manufacture of Sterile Medicinal Products

Revision 14 February 2008Revision 14 February 2008

Aim of the revision: •

Keep pace with technological change;

•

Solve some interpretation problems

•

Harmonize with the ISO guidelines and FDA regulations.

4

Revision Annex 1Introduction

•

Classification of Cleanrooms;

•

Media Fill execution method;

•

Advices concerning bioburden for sterilization loads;

•

Advices concerning capping of vials.

The Annex 1 of EC Guide to GMP, “Manufacture of Sterile Medicinal Products, has been recently reviewed (February 2008) concerning on the following topics:

Annex 1 becomes effective on March 1st, 2009, except for capping, in order to give enough time to industry to set on the new requirements; this part will be active starting from March 1st, 2010.

5

•

“Production of sterile products is subject to special requirements in order to minimize the risk of microbial and pirogen

contamination.

•

Sterile areas should have an appropriate cleaning standard with air passing through efficient filters.”


Two different methods of production

Aseptic production

Production with final sterilization

Volume 4, EU GMP, Annex 1“Manufacture of Sterile Medicinal Products”

February 2008

“Where possible, heat sterilization is the method of choice”

6

•

Grade A: The local zone for high risk operations. Laminar air flow systems should provide a homogeneous airspeed in a range of 0.36 –

0.54 m/s

(guidance value) at the working position in open cleanroom applications;

•

Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone;

•

Grade C e D: Clean areas for carrying out less critical stages in the manufacture of sterile products.


For the manufacture of sterile medicinal products 4 cleanroom cleanliness grades can be distinguished:

Volume 4, EU GMP, Annex 1 -

“Manufacture of Sterile Medicinal Products”

February 2008

7


Examples of operations to be carried out in the various grades:

Grade Examples of operations for terminally sterilised products.

A Filling of products, when unusually at risk

C Preparation of solutions, when unusually at risk. Filling of products

D Preparation of solution and components for subsequent filling

Grade Examples of operations for aseptic preparations.

A Aseptic preparation and filling

C Preparation of solution to be filtered

D Handling of components after washing



February 2008

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The requirements for classification are clearly defined

Routinary

monitoringInitial Classification

The following is applied to

Clean Air Devices

(hoods, LAF, isolator, RABS,…)

Cleanrooms

Revision Annex 1Cleanrooms Classification

9

Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1; the table for particles limits has (almost) been

harmonized with itMaximum permitted number of particles per m3 equal to or greater than

the tabulated size

At rest In operation

Grade 0.5µm 5.0 µm 0.5µm 5.0 µm

A 3520 20 3520 20

B 3520 29 352000 2900

C 352000 2900 3520000 29000

D 3520000 29000 Not detect Not detect



February 2008

For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the classlimit of the largest considered particle size and the method of evaluation of

the data collected


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ISO 14644-1

N. Sampling points N = (m2)

Sampling Volume Vs =__20__

(m3)Cmax

ISO Classification number (N)

Maximum concentration limits (part/mc)

0,1 μm 0,2 μm 0,3 μm 0,5 μm 1 μm 5 μm

Class 1 10 2

Class 2 100 24 10 4

Class 3 1 000 237 102 35 8

Class 4 10 000 2 370 1 020 352 83

Class 5 100 000 23 700 10 200 3 520 832 29

Class 6 1 000 000 237 000 102 000 35 200 8 320 293

Class 7 352 000 83 200 2 930

Class 8 3 520 000 832 000 29 300

Class 9 35 200 000 8 320 000 293 000

AI.e. a sampling volume adequate to capture 20 particle at the upper limit of the class.


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An important topic for revision is the requirement on particle size ≥

5.0 µm.

FDA does not plan to monitor them, while for EMEA it is a valid "diagnostic tool" to track the loss of benefits of the cleanroom and to report the incidence of abnormal situations not easily detectable by other parameters.

The Annex 1 has retained the obligation to control the particle sized ≥

5.0 μm, establishing a limit of 29 part/m3 for grade B at rest.

Despite that, the limit for such particles for grade A, formerly

of ≤

1 part/m3

was changed to ≤

20 part/m3:

“The occasional indication of ≥5.0 μm particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor practices during machine set-up and routine operation.”

Particle size ≥

5.0 µm



February 2008


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Grade“at rest” “in operation”

Particles ≥

0.5µm

Particles≥

5µm

Particles ≥

0.5µm

Particles ≥

5µm

A 3.520 (3.500)

20 (1)

3.520 (3.500)

20 (1)

B 3.520 (3.500)

29 (1)

352.000 (350.000)

2.900 (2.000)

C 352.000 (350.000)

2.900 (2.000)3.520.000

(3.500.000)29.000

(20.000)

D 3.520.000 (3.500.000)29.000

(20.000)No defined No defined

(limits set in 2003 revision of Annex 1 are between brackets)

Comparison between particles limits (n. part./m3)

Annex 1 (2003) vs. Annex 1 (2008)


13

5. “For classification purposes in Grade A zones, a minimum sample volume of 1m3

should be taken per sample location.”Volume 4, EU GMP, Annex 1 -


February 2008

Sampling Volume

•

In the 1997 edition of annex 1 the limit for particles ≥5.0 μm

was “0”

and

there were not any indication about the sampling volume, so the ISO 14644-1 formula was applied to 0,5 μm particles (0,1 ft3

could be enough, typically 1 ft3

was used).•

In the 2003 revision the limit was established as “1”

(specifying that 0 have not a statistical significance) and the correspondent test about the sampling volume was:“For routine test the total sample volume should not less than 1 m3 for grade A and B areas and preferably also in grade C areas”.This request was often applied to the whole area instead of each

sampling point.

•

The new 2008 revision:–

moves the 1 m3

sampling volume application from the routine monitoring to the “classification purpose”

sampling;–

limits the request to the grade A areas, with just an option for

grade B areas;–

specifies that 1 m3

sampling volume should be “taken for sample location”.


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“For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 μm.

For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes.

For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively.

For Grade D (at rest) the airborne particle classification is ISO 8.

For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.”



February 2008

Correspondence with ISO 14644-1


15


In practice we can interpret it…

•

The Grade A represents the ISO 5 class for particles ≥

0.5 μm

and a “ISO 4.8”

class for ≥

5 μm particles

•

Grade B at rest

corresponds to ISO 5, in operation to ISO 7. There are some

interpretative doubts on the limit for Grade B at rest, which would lead to a theoretical sampling volume of about 0.7 m3; it seems logical to interpret this requirement so as to use a sample volume of 1 m3

also able to B.

•

For Grade C (corresponding to ISO 7 at rest

and ISO 8 in operation) and D

(corresponding to ISO 8 at rest), however, due to the clear reference to ISO 14644-1, nothing prevents you from taking a “typical”

sample volume of 1 ft3

for "sampling location".

Correspondence with ISO 14644-1

16

The 2008 EU GMP Annex 1:

•

defines how to count the particles in operation

(or during the routine production or during a Media Fill simulation); also refers to the ISO 14644-2 regarding the frequency of repetition of tests for grading;

•

it requires that points to be monitored in operation are determined on the basis of risk analysis and the results of the classification;


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Routine Cleanrooms monitoring:

•

the sampling volume is accepted to be different from that used for

classification, encouraging to use a sampling rate appropriate to report transient spikes of contamination (and therefore should be possible not to sample 1 m3

in class A and B, but use repeated smaller volume samples;

•

Class A is supposed to have a continuous sampling

at all critical stages of production;

•

Class B admits a less frequent control, based on the effectiveness of segregation of the zone A compared to zone B;

•

Annex 1 implicitly does not recommend the use of particulate samplers like "manifold“, because an excessive length and too many curves of the sampling tube cause a decrease in collection efficiency of larger particles


18

Routine Cleanrooms monitoring:

•

Monitoring in grade A is tolerated to be interrupted in case of process phases in which hazardous contaminants are present (e.g. radiopharmaceuticals, living organisms, viruses);

•

it admits that sampling near the point of filling bottles can produce off-specification values for ≥

5.0μm particles, although the trend of

the inspectors is to suggest that there are engineering solutions to avoid this problem, and therefore we assume that they are available in industry;

•

Finally, the need to define a recovery time of class after the

completion of the transactions is required; this would allow to return to the particles conditions set out for "at-rest" after 15-20 minutes.

Revision Annex 1Cleanrooms Routine Monitoring

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9. “For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk.

Monitoring during simulated operations should also be performed.

The Grade A zone should be monitored at such a frequency and with suitable sample

size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 μm

particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.”

10. “It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.”



February 2008


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Recommended limits for microbial contamination (a)

Grade Air sample cfu/m3

Settle plates (diameter 90 mm)

cfu/4 hours (b)

Contact plates (diameter 55

mm) cfu/plate

Glove print 5 fingers

cfu/glove

A <1 <1 <1 <1

B 10 5 5 5

C 100 50 25 -

D 200 100 50 -

No significant news emerge relative to microbial contamination, the limits have remained unchanged, and no explanation has been given to the fact that they are referred to mean values, important point of difference from the U.S. legislation



February 2008


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Revision Annex 1Blow/fill/seal

Blow/fill/seal machine should be installed in class C areas. Manufacturing machine for final sterilized products should be installed in class D areas.

27. “Because of this special technology particular attention should be paid to, at least the following:

•

equipment design and qualification;•

validation and reproducibility of cleaning-in-place and sterilisation-in-

place;•

background clean room environment in which the equipment is

located;•

operator training and clothing;

•

interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling”.



February 2008

Blow/fill/seal units are purpose built machines in which, in one

continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine.

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Revision Annex 1Media Fill

Paragraphs on Media Fill have been expanded:

66. “Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium”.

67. “The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst-case situations”.

68. “Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process”.



February 2008

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Limits of number of contaminating units depending on total filled units, are defined:

69. “The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:

•

When filling fewer than 5000 units, no contaminated units should

be detected.

•

When filling 5,000 to 10,000 units:a)One (1) contaminated unit should result in an investigation,

including consideration of a repeat media fill;b)Two (2) contaminated units are considered cause for

revalidation, following investigation.

•

When filling more than 10,000 units:a)One (1) contaminated unit should result in an investigation;b)Two (2) contaminated units are considered cause for

revalidation, following investigation”.



February 2008

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An investigation of microbiological contamination events is required for any size Media Fill executed; even if the contamination detected is low, but not zero, the cause should be clarified. If instead the Media Fill highlights problems of contamination (e.g. Beyond the limits specified), an analysis

of their impact

on sterility of batches of product processed starting from the last Media Fill succeeded until then, is required.

70. “For any run size, intermittent incidents of microbial contamination may be indicative of low-level contamination that should be investigated. Investigation of gross failures should include the potential impact on the sterility assurance of batches manufactured since the last successful

media fill”.



February 2008

Requirements concerning Media Fill

have been “harmonized”

with FDA.

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Revision Annex 1Bioburden

80. The bioburden should be monitored before sterilisation. There should be working limits on contamination immediately before sterilisation, which are related to the efficiency of the method to be used.

Bioburden assay should be performed on each batch

for both aseptically filled product and terminally sterilised

products.

Where overkill sterilisation

parameters are set for terminally sterilised

products, bioburden might be monitored only at suitable scheduled intervals.

For parametric release systems, bioburden assay should be performed on each batch and considered as an in-process test.

Where appropriate the level of endotoxins should be monitored.

All solutions, in particular large volume infusion fluids, should be passed through a micro-organism-retaining filter, if possible sited immediately before filling.



February 2008

26

Revision Annex 1Capping of vials

The most relevant variation in the new Annex 1, considering impact on pharmaceutical products, regards the classification of the zones where capping of vials is performed.

These requirements are applied to each final form of sterile product:

•

Lyophilized

•

Liquids

•

Powders

27

Vials of products that are partially stoppered, should be kept in Grade A zone until the stopper is completely inserted; this obvious requirement was already effective in practice.

116. “Partially stoppered

freeze drying vials should be maintained under Grade A conditions at all times until the stopper is fully inserted”.




February 2008

28

118. “The container closure system for aseptically filled vials is not

fully integral until the aluminium cap has been crimped into place on the stoppered

vial.

Crimping of the cap should therefore be performed as soon as possible after stopper insertion”.

120.“Vial capping can be undertaken as an aseptic process

using sterilised caps or as a clean process

outside the aseptic core. Where this latter

approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter

stoppered

vials should be protected with a Grade A air supply until the cap has been crimped.”



February 2008


Until the previous revision, Annex 1 did not require to cap the vials in a specific grade zone; in the industrial practice, it was usually performed

in grade D or C,

with a local LAF protection on the machine and the conveyor belt.

The approach of the new Annex 1 have precise requirements

29

b.

Capping could be performed as a “clean”

instead of an aseptic process; in this case, vials should be protected during their transfer from the filling machine to the capping machine, until their complete closure.

The capping machine is allowed to be installed out of the sterile area, but the conveyor belt should stay inside the grade A zone until the exit

from the sterile

area; for the machine and the part of the belt outside the sterile area, a grade A air flow protection is required, without a specific requirement for a grade B background.

Paragraph n°122 suggests some options; among them, “RABS”

and isolators are mentioned as devices able to ensure the required conditions and minimize human intervention and, consequently, a possible contamination.

122. “Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation”.



February 2008


30

In case the capping is performed as “aseptic process”, inside the sterile zone, it means…

• equipment suitable to be installed in a sterile area

(materials, finishing, maintenance mode, etc ...)

• personnel dressed with clothes for aseptic area

• microbial and particles monitoring (!!!)

• material’s paths suitable in the aseptic area

…

especially …

• Sterile caps and manipulated so as to maintain the sterility of the cap itself and the background environment (!!!)


31

119. “As the equipment used to crimp vial caps can generate large quantities of non-viable particulates, the equipment should be located at a separate station equipped with adequate air extraction”.



February 2008

Note: capping machine should be separated from filling machine, in order to avoid contamination in the filling zone


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Another problem identified in the development of the new Annex 1

is the possibility of manual "not allowed" operations performed on partially closed bottles, for example, repositioning or replacement of poorly placed caps, which can lead to significant danger of contamination of the product .

Hence the request to provide identification systems for the capping machines, and the automatic discarding of bottles with missing or badly positioned caps before the corking, and to provide adequate systems to minimize the microbiological contamination in case of need for human intervention, such as precisely barrier or insulators systems.

In any case human intervention should be minimized.

121. “Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimise

microbial contamination”.



February 2008


33

Revision Annex 1Conclusions

•

“Risk Based”

approach for interpretation of the new requirements;

•

Harmonization with international standards;

•

A considerable change with high impact regarding the capping.

Doubts expressed by many European operators in the fields are shown (both manufacturers of finished drugs and manufacturers of packaging machinery) on the possibility to fully comply with the new requirements in less than two years, considering difficulties due to the need for considerable

investment and

technological difficulties.

Revisione Annex 1Risorse in rete

Annex 1, revision

2008

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-

en/2008_02_12_gmp_annex1.pdf

Comparison

between

old

and new

Annex 1

http://www.gmp-

navigator.com/elements/PDF/Gegenueberstellung_Annex_1_Feb_08.pdf

Thank you for your kind attention

[email protected]

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