CO M P LY LYI N G
WITH INTERNATIONA INTERNATIONAL L CLEANROOM STANDARDS / GMPs
without getting ulcers Shee Sheesh sh Gula Gulati ti Measu MeasureT reTest est Corp Corpora oratio tion n
MULTIPLICITY OF STANDARDS / GUIDELINES • • • • • • • • • •
F.S.209E ) Antique value? BS 5295 ) IEST RP-CC-034.1 PDA Technical Report 13 USP 797 Sterile compounding TGA Guidelines for Sterility testing Annex IV PIC/S ISO 14644 US FDA FDA cGMP cGMP Asepti Aseptic c Proces Processin sing g EU GMP Annex 1
MULTIPLICITY OF STANDARDS / GUIDELINES • • • • • • • • • •
F.S.209E ) Antique value? BS 5295 ) IEST RP-CC-034.1 PDA Technical Report 13 USP 797 Sterile compounding TGA Guidelines for Sterility testing Annex IV PIC/S ISO 14644 US FDA FDA cGMP cGMP Asepti Aseptic c Proces Processin sing g EU GMP Annex 1
WHICH STANDARDS TO FOLLOW? Questions to ask about Standards:
• • • • • • •
What is th Wha the e so sour urce ce of th the e st stan and dar ard? d? Is it required? Shou Sh ould ld it be re requ quir ired ed? ? Ca Can n I eli elimi mina nate te it it? ? Does Do es th the e sta stand ndar ard d ref refle lect ct cu curr rren entt tec techn hnol olog ogy? y? Is it relevant to my product? Are Ar e the there re ne newe werr stan standa dard rds s that that ar are e mor more e rel relev evan antt ? Is the the sta stand ndar ard d suff suffic icie ient nt to to ach achie ieve ve the the req requi uire red d performance? • Is it realistic? • Do Does es th the e sta stand ndar ard d have have a pot poten enti tial al ne nega gati tive ve ef effe fect ct on
FEDERAL STANDARD 209E OBSOLETE
• F.S. F.S.20 209, 9, fo forr 40 40 yea years rs th the e mai main n def defin init itio ion n of of cleanroom clean room class classificat ification ion level levels, s, was offic officially ially cancelled in 2001 • Replaced by ISO 14644 • The The mai main n dif diffe fere renc nces es be betw twee een n FS FS 209 209 an and d ISO 14644 and how the new standards affect the phar pharma ma ind indust ustry ry is discu discusse ssed d in the next next few slides
COMPARISON OF ISO 14644-1 WITH FS 209 ISO 14644-1 ISO Class
FED STD 209E English
Metric
1
ISO 14644-1 adds
•
2
2 “ultra-clean” classes – ISO Class 1
3
1
M1.5
4
10
M2.5
5
100
M3.5
6
1,000
M4.5
– ISO Class 2 •
1 “very dirty” class – ISO Class 9
Total of 9 classes Counts / cubic metre
7
10,000
M5.5
8
100,000
M6.5
9
Must specify room status
•
“as-built” / “at rest” / “in operation”
- specify particle size/concentration
ISO 14644-1 COUNT LEVELS
Airborne Particulate Cleanliness Classes (by cubic metre)
CLASS
Number of Particles per Cubic Metre by Micrometre Size >= 0.1 um
Old Class 100>
0.2 um
0.3 um
0.5 um
1 um
5 um
ISO 1
10
2
ISO 2
100
24
10
4
ISO 3
1,000
237
102
35
8
ISO 4
10,000
2,370
1,020
352
83
ISO 5
100,000
23,700
10,200
3,520
832
29
ISO 6
1,000,000
237,000
102,000
35,200
8,320
293
ISO 7
352,000
83,200
2,930
ISO 8
3,520,000
832,000
29,300
ISO 9
35,200,000
8,320,000
293,000
ISO CLEANLINESS LEVELS Points to note:
• Each successively higher ISO classification allows approximately ten times as many particles as the previous class • The ratio of particles of size A to size B remains approximately constant for all classes. Example: Class 4 allows 10,200 particles ≥0.3 µm or 3,520 µm ≥0.5 µm Class 5 allows 102,000 particles ≥0.3 µm or 35,200 ≥0.5 µm
ISO 14644 CLASSES A common mistake is to assume that, because sizes of 0.1 micron, 0.2, 0.3, 0.5, 1 & 5 microns are given in the Classification Table, we have to check all these particle sizes. The considered particle size(s) for which the concentration will be measured, shall be agreed upon by the customer and the supplier. Each larger particle diameter shall be at least 1.5 times the next smaller particle diameter. In the pharmaceutical industry, normally one checks
25 microns particles? The main reason 25 microns was historically required for users is due to the BS 5295 standard [U.K.] that required monitoring at 25 microns. In the USA, the need for 25 microns was muted. Several other EU countries also leaned on the BS 5295 standard before ISO 14644-1 was introduced in 1999, and for a few years after. Note that 25 microns is specified within BS 5295 for the equivalent of ISO Class 8 (Class 100K) and ISO Class 9. These are "dirtier" environments. For BS 5295 Class J (ISO Class 8), the limit was zero per cubic metre and for BS 5295 Class K (ISO Class 9), the 25 micron limit was 500/cubic metre. For cleaner areas below ISO Class 8/Class 100K, the chart in BS 5295 is marked as "NS" for "No Specified Limit".
Certification: ISO 14644-1 versus FS 209E Parameter
FS 209E
ISO 14644-1
Minimum sample volume
2.83 litre (0.1 cubic foot)
2.0 litre (0.07 cubic foot)
Minimum sample time
not specified
1 minute
Minimum number of samples at each location
2 with at least 5 samples total
1 with at least 3 samples total
Note: Typical sample volume may be larger than minimum listed above especially for smaller size particles in very clean areas (better than ISO
ISO 14644-1 Minimum Sample Time at 1 CFM Time required (in minutes) at 1 cfm (28.3 lpm) flow rate with 1-minute limit imposed 0.1 um
0.2 um
0.3 um
0.5 um
1 um
5 um
ISO Class 1
70.64
353.20
ISO Class 2
7.06
29.43
70.64
176.60
ISO Class 3
1.00
2.98
6.93
20.18
88.30
ISO Class 4
1.00
1.00
1.00
2.01
8.51
ISO Class 5
1.00
1.00
1.00
1.00
1.00
24.36
ISO Class 6
1.00
1.00
1.00
1.00
1.00
2.41
ISO Class 7
1.00
1.00
1.00
ISO Class 8
1.00
1.00
1.00
Cleanroom Certification Initial and periodic certification
• Federal Standard 209E (previously) • ISO 14644-1, -2 (now) • Max time interval for ISO Class 5 is 6 months Three states
• As-built • At Rest • Operational / Dynamic Averaging of Data from all positions permitted
Certification: FS209E and ISO 14644-1 •
Defines Cleanroom classes
•
Establishes minimum sampling volumes
• purpose: to gather a sample volume with theoretically at least 20 particles to help with statistical validity of sample •
Establish minimum number of points to classify area, based on statistical criteria
• Certification is also referred to as Classification or validation or Verification
Monitoring vs. Certification (Qualification) EC or GMP focus: parameters during operation
• dynamic or “in operation” • potential effect on product is critical issue but Certification is normally done during idle time
• infrequent but thorough check of the environment • “as-built” • “at rest” Greatest concern for FDA is for viable microorganisms
• Technology is not available today to measure viable counts in real time
U.S. FDA AND ISO 14644 • FDA welcomes new ISO standards as one harmonised, base-line document on the subject of air cleanliness classification is better than five with small but difficult to reconcile differences • ISO documents are generic, non-industry specific, written to meet multi-constituent industries, and often the result is the dilution of standards to the lowest common denominator • A company may meet the criteria of ISO 14644 but that does not mean they are complying with cGMPs. According to FDA, classification of a clean area is based not only on particle concentration but also on microbiological data
FDA prohibits averaging across positions
“A”
“B” for 2 positions in ISO Class 5 (FS 209E Class 100) ...
125
3
119
8
120
12
364 >> 121
FDA says 65
8 << 23
Placement of Sample Probes •
No regulatory standards for monitoring
•
Not controlled earlier by FS 209E or now by ISO 14644-1, when conducting monitoring of the process
• Costly and not practical to establish monitoring points based on the ISO 14644 formula of square root of area in sq.metres. Risk assessment is very important in determining where to monitor
ISO Class 5: ISO 14644-1 Classification Calculations Vial Washing System
Freeze Dryer 1
5m
Freeze Dryer 2
8m
Calculations for Number of Points:
5m
Freeze Dryer 3
Area of clean zone = 80 m² Take the SQRT (80) = 8.94 Rounding up to next integer = 9 sample positions
4m
ISO Class 5: ISO 14644-1 Classification Calculations Vial Washing System
Freeze Dryer 1 1
2
3
4
5
6
7
Calculations for Number of Points:
Freeze Dryer 2
8
Area of clean zone = 80 m² Take the SQRT (80) = 8.94 Rounding up to next integer = 9 sample positions
9
We might place them as shown. But this does not take into
Freeze Dryer 3
ISO Class 5: ISO 14644-1 Calculations 1
2
Vial Washing System
3
4
5
6
7
8
9
10
Freeze Dryer 1
Freeze Dryer 2 Need to adjust for equipment in room. Under ISO 14644-1, if you sample at 10 or more positions, you can avoid the added calculation of the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9. Best to sample near potential problem spots which are near entrances and exits and near operator positions.
Freeze Dryer 3
ISO Class 5: ISO 14644-1 Calculations 9
Vial Washing System
1 10 8
Freeze Dryer 1
2 11 3
4
5
6
7
12
Freeze Dryer 2
14
Freeze Dryer 3
Need to adjust for equipment in room. Under ISO 14644-1, if you sample at 10 or more positions, you can avoid the added calculation of the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9. Best to sample near potential problem spots which are near entrances and exits and near operator positions.
Here could be a distribution of sample points that would both
13
Placement of Isokinetic Probes in a Pharmaceutical Filling Area for the Purpose of Monitoring—
What you won’t find in any book !
EU Annex I: Selecting Monitoring Positions ISO Class 5 6
Vial Washing System
1
Freeze Dryer 1
5 2 7 3
4
Presence of lyophilizers indicate vials may not be fully stoppered so the holding position near “5” represents some risk Position “6” provides evaluation of Grade B zone and probably early indication of pressure balance problems due to proximity to doors Positions “7” and “8” are needed because loading area in front of lyophilizers should be Grade A if product is not fully stoppered
Freeze Dryer 2 8
Freeze Dryer 3
EU Annex I: Selecting Monitoring Positions 5
Vial Washing System
1
2
3
4
If this were a filling operation for which the final product remains liquid i.e. freeze dryers were not present, some points would not be needed.
Placement of Isokinetic Probes in a Life Science Manufacturing Area (ISO Class 7 or 8)
Example: Cleanroom Area ISO Class 7 or 8 Classification
How to choose sampling points?
100 ft (30 m)
175 feet (53 m)
This is is a large area of of 30 metres by 53 metres, metres, and rated rated as an ISO Class 7 or Class 8 (FS209E Class 10K or 100K).
ISO Class 7: ISO 14644-1 verification
Entry plane (m2): 1590 m2 100 ft (30 m)
SQRT (1590) = 39.87 Minimum sample points = 40
175 feet (53 m)
Following the ISO 14644-1 methods, we would determine that the minimum number of sample points to carry out a formal verification would be 40.
ISO Class 7: ISO 14644-1 verification
Entry plane (m2): 1590 m2 100 ft (30 m)
SQRT (1590) = 39.87 Minimum sample points = 40 6x7 grid = 42 175 feet (53 m)
But this is not an easy number number to set up for a grid pattern in a rectangular area so forty-two positions might be a better choice.
ISO Class 7: ISO 14644-1 verification
Entry plane (m2): 1590 m2 100 ft (30 m)
SQRT (1590) = 39.87 Minimum sample points = 40 6x7 grid = 42 175 feet (53 m)
The sample positions would be at work height in the middle of each rectangle.
Example: ISO 14644-1 Calculations 1. Sum and average values at each position 2. Calculate the mean of averages 3. Result must be less than – a) the limit for the given size and – b) target room classification
If the number of points sampled is more than 1 but less than 10, then the UCL factor must be applied:
• • • • •
Calculate the standard deviation Use Student’s T-factor from tables Calculate UCL Compare to classification limit UCL must not exceed the applicable limit
ISO Class 7: Selecting Monitoring Positions Work Station 1
Work Station 2
Storage
100 ft (30 m)
Work Station 3
Work Station 4
175 feet (53 m)
In the real world, monitoring positions will be affected by the physical layout of the area and the activities that occur within it.
ISO Class 7: Selecting Monitoring Positions Work Station 1
Work Station 2
Storage Work Station 3
Work Station 4
175 feet (53 m)
Monitoring should focus on the product exposure and vulnerability: “Where in the process is my product that most vulnerable to contamination because of a) the length of time it sits exposed to
100 ft (30 m)
Where to monitor – PIC/S recommendations Pharmaceutical Inspection Convention, Geneva
Recommendation on the Validation of Aseptic Processing states: Ensure that location chosen for non-viable monitoring reflects the worst case For room monitoring, counts should be performed in locations where there is most operator activity For the filling environment,counts should be performed adjacent to the filling zone and where components are exposed in such a way as to detect operator activity within these areas
Where to monitor -- PIC recommends •
Avoid monitoring in such a way that the probes monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones
•
Location of the sample device should not compromise the the laminarity of the air flow in the critical zone
FDA GMP:
•
Measurements should be taken with the particle counting probe oriented in the direction of oncoming airflow and at the sites where there is most potential risk to the exposed product
Where to monitor?
Where to monitor in ISO Class 5 (Class 100) / Grade filling room
General wisdom is to monitor wherever an operator is known to breach the sterile zone with his arm or body Typically this may be the following 3 areas : descrambler table, near the filling needle mechanism, and the stoppering process Some filling machines often incorporate these functions in a more compact area and thus only one or two positions are practical
Placement of Sample Probes 1.
Sample near to exposed product • •
Generally near work height and exposed product If liquid sterile fill, guidance is to sample air approaching the product within 12” (30 cm) of exposed
Do Not measure directly above critical point • •
Starves the are of air Creates turbulence
Measure to one side, close to critical location
2. Sample near to points of intervention by operators
Examples: • Descrambler table • Filling needles • Stoppering process
Less than 12 inches (30 cm)
Probe Sampling Positions Isokinetic probe on an Accumulation Turntable provides monitoring of rotary in-feed turntable after sterilization zone. Adjustable mount (optional) allows fine tuning of sampling position. Probe shown with Cap in place
Probe Sampling Positions Iso kinetic sampling under the HEPA Filter in a Shrouding Machine Isokinetic probe cups can be mounted up to 3 metres from the counter Each probe is connected to the counter via a Hytrel non shedding tubing.
EC GMP Guide Annex 1 – Sterile products Version effective September 2003 stated:
• Limit of 5 micron particles for Grade A is 1 per cu.metre in operation and for Grade B at rest • Continuous measurement system should be used for Grade A areas (and recommended for Grade B) • For routine testing , total sample volume should not be <1 m³ for Grade A & B areas; preferably also in Grade C areas
REVISION OF EU-GMP GUIDE Comments: Research on size distribution of particles in a cleanroom has shown that when 3500 particles of 0.5 micron are present per cu.metre, it will contain more than one particle of 5 micron. The well established, and confirmed, size distribution curve used in the ISO standard predicts 29 particles. Therefore this stipulation was illogical and led to protests from industry
EU-GMP ANNEX 1 2003 REVISIONS • The use of the word "continuous" was misleading; the right interpretation was “periodic automated sampling” Sampling intervals of 5 to 10 minutes are all right, whereas 35 to 40 minutes would be too long. • The regulators feel that there should be zero 5 micron particles in the room, but realise that there can be occasional "outliers". However, they expect people to react to trends of frequent or high readings. So, the occasional count of "1" or "2" should not stop the line. Constant readings of say 20, should cause an investigation.
CLASSIFICATION ACCORDING TO 0.5 MICRON If we were just considering 0.5 micron particles, both ISO and US FDA would permit a sampling volume of
Vs = 20/Cn.m x 1000 where Vs = Volume in litres, Cn.m = number of particles/m3 for the relevant class Therefore Volume of sample = 20/3520 x 1000 = 5.68 litres With a particle counter of flow rate 1 cfm (28.3 lpm), time taken would be less than 1 minute, so we would run the particle counter for just 1 minute.
1 PARTICLE OF 5 um IN QUALIFICATION
Now let us see what happens if we were to consider 5 micron particles also.
Using the same formula, volume per location according to ISO 14644 would be : 20/29 x 1000 = 690 litres At sampling rate of 1 cfm (28.3 litres/mim), this would take only 24 minutes Which is still quite reasonable
BUT WHAT HAPPEN WITH EC GMP LIMIT OF ONE PARTICLE OF 5 um Volume required per location would be:
20/1 x 1000 = 20,000 litres Time required per location at sampling rate of 28.3 l/min = 706 minutes
= 12 hours approx!
This made Certification of your cleanroom much more expensive and time consuming. Latest 2008 revision therefore relaxed limit to 20 particles instead of 1 particle of 5 microns/cu.metre
EU GMP LATEST REVISION 2008 On 14th February 2008, the European Commission updated Volume 4 of EU Guidelines to the GMPs for medicinal products for Human and Veterinary use This revised Annex 1 will come into operation on 1 st. March 2009 except for the provisions on capping of freeze-dried vials, which should be implemented by 1 st. March 2010. It clearly outlines three phases that need to be performed: Certification: Each cleanroom and clean air device should first be classified Monitoring: the cleanroom should then be monitored to verify that conditions are being maintained relative to product quality Data Review: Ensure that the data accrued from the monitoring be reviewed in the light of risk to finished product quality.
EU GMP LATEST REVISION 2008 The maximum permitted airborne particle concentration for each grade is given in the following table Maximum permitted number of particles per m3 equal to or greater than the tabulated size At rest
In operation
Grade
0.5 µm
5.0µm
0.5 µm
5.0µm
A
3 520
20 (ISO 5 = 29)
3 520
20
B
3 520
29
352 000
2 900 (ISO 7 =2930)
C
352 000
2 900 (ISO 7 = 2930)
3 520 000
29 000 (ISO 8 = 29,300)
D
3 520 000
29 000
Not
Not defined
EU GMP 2008 REVISION
Continuous Discontinued? The new revision does not specifically mention Continuous Measurement Systems are mandatory, but it is implied : “For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly” “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”
EU Annex 1: March 2009 Changes At Rest
In Operation
Grade Maximum permitted number of particles/m 3 equal to or above 0.5 µm
5 µm
0.5 µm
5 µm
A
3 500
1
3 500
1
B
3 500
1
350 000
2 000
C
350 000
2 000
3 500 000
20 000
D
3 5000 000
20 000
not defined
not defined
At Rest
Existing Effective Sept. 2003
5 µm limits for Grade A & B
0 1 per cubic meter
In Operation 3
Grade Maximum permitted number of particles/m equal to or above 0.5 µm
5 µm
0.5 µm
5 µm
A
3 520
20
3 520
20
B
3520
29
352 000
2 900
C
352 000
2 900
3 520 000
29 000
New Effective Mar. 2009
5 µm limits for Grade A
1 20 per cubic meter
Why measure 5 um particles ? EU inspectors maintain that large particles are potential carriers (hitch-hikers), of or are, viable organisms themselves. If these particles are present in an aseptic environment, they represent an increased risk of contamination of the sterile product. Large particles do not transport well in tubing runs exceeding 3 metres (10 feet). Keep tubing runs from the sample site to the particle counter as short as possible to avoid particle loss. 5 micron counts can be an indicator of:
• Problems with the physical plant
SEQUENTIAL MANIFOLD SYSTEMS 1.
2.
Although manifold type sequential monitoring systems are not banned, it will be difficult to justify the use of manifolds after 1st.September 2003. Evidence might be expected that manifold systems had documented efficiency at larger particles… “the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing.” “I believe that our intention was not to ban cyclical sampling. By continuous we meant throughout the filling run. But we would expect, again, for the sampling regime to be documented; the rationale explained and justified. … if you had a cyclical manifold and it was sampling in the Grade A zone once every 45 minutes, then you might have a bit of a problem justifying that. If it is sampling, for example, every 5 minutes, the justification would be very much easier to write.”
Why EC GMP doesn’t like Manifolds T u b i n g T r an s ppo o r t L os s 100 90 80 % L o s s
0,1 µ
70 60
0,5 µ
50
1µ
40 30
3µ
20 10
10 µ
0,7 µ
5µ
0 2
7
13
19
Length of tubing (meters)
26
30
EU Annex 1 2008 Revision Summary For verification ( classification of room) Section 3: (Enhanced definition of at rest) “The “at-rest” state is the condition where the installation is installed
and operating, complete with production equipment but with no operating personnel present.”
Section 4: “Classification should be clearly differentiated from operational process environmental monitoring.”
Section 5: “For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the [minimum] sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected” “For classification purposes in Grade A zones, a minimum
EU Annex 1 2008 Summary For monitoring (for example, with an FMS system) there is no minimum volume or time period for each sample In Annex I, the only statements are to
• encourage a continuous sampling system for the Grade A areas • encourage a continuous sampling system for the Grade B areas, although not so necessary as for Grade A • indicate that the sample rate can be different than that used to qualify the area Section 12 states:
"It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.“ i.e. you do not need to sample minimum 1 cu metre during monitoring
DEALING WITH 1 CU.METRE REQUIREMENT DURING CLASSIFICATION Increased sampling frequency of low air volume is preferable to high air volume at low frequency In other words, 35 readings of 1 minute at 1 cfm are preferable to 1 reading of 35 minutes Action limit for 1 cu.metre Single readings: If all readings are below 1/35 of the limjt, the limit will never be exceeded Multiple readings: If some of the single readings exceed the 1/35 of cu.metre limit, it has to be checked whether the result of sampling 1 cu.metre air volume would have exceeded the limit
DEALING WITH 1 CU.METRE REQUIREMENT DURING CLASSIFICATION Action limit for 1 cft readings: Readings below 1/35 of the 1 m3 requirement are acceptable • 100 counts/cft for 0.5 micron • 0 counts/cft for 5 microns Any reading exceeding 1 m3 requirement is not acceptable: 3521 counts for 0.5 micron & 21 counts for 5 micron particles
SUGGESTED PARTICLE MONITORING REGIME • Sample size and frequency should be based on likelihood of finding a contamination event
• A long sample time --and hence large volume – could allow a short term even to be diluted by a low subsequent count rate
• A short sample time alone might cause you to think a false or spurious count is a real major contamination event
• Correlation with media fill data? Usually unlikely
SUGGESTED PARTICLE MONITORING REGIME Considering the >= 5 micron particles,
• EU GMP limit is 20 per cu metre • 1 cu metre takes about 36 minutes to sample at I cfm i.e. 28.3 lpm • If we wait 36 minutes before evaluating a sample, we could miss an event • If we only look at a small sample of 1 cft (28.3 litre), then 1 real or false particle would imply 35/cu metre = FAILING the 20 limit • So we should look simultaneously at each 28.3 litre sample and a cumulative 1000 litre (1 m3) sample
EU GMP -- VIAL CAPPING ISSUES • Relates to freeze dried products, liquid and solid fill applications
• Concerns were raised by inspectors when seeing mis-placed stoppers re-seated by hand or even stoppered by hand when missing
• Partially stoppered freeze dried vials “maintained under Grade A conditions at all times”
• Non-freeze dried vials “protected with a Grade A air supply”. Is protected the
EU GMP – VIAL CAPPING •
Containers should be closed by appropriately validated methods. Containers closed by fusion e.g. glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures
•
Partially stoppered freeze drying vials should be maintained under grade A conditions at all times until the stopper is fully inserted
•
The container closure system for aseptically filled vials is not fully integral until the aluminium cap has
EU GMP – VIAL CAPPING •
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
•
Vial capping can be undertaken as an aseptic process using sterilized 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.
EU GMP – VIAL CAPPING • Note that a Grade A air supply is differentiated from a Grade A environment • Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is requires at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimize microbial contamination • This part of Annex 1 will be effective from
Interference from capping operation Unidirectional air shower
Higher sample probe for monitoring during capping operation
Sample probe to demonstrate air quality before capping process
s s e n L h a m t m 5 0 3
Interpreting EU GMP Annex 1 – the PHSS Best Practice Guide (Pharmaceutical & Healthcare Sciences Society, U.K.)
Advice on Best Practice for Cleanroom Monitoring None in Annex 1 – What system to use? – Where to locate monitoring points? – How do we deal with 5μm counts? – 1m3 volume during manufacture? – Powder fill applications?
FDA cGMP – “areas where product is at most potential risk” – “not more than 1 foot away from the work site”
Advice on Best Practice for Cleanroom Monitoring What was lacking was practical advice on how to implement these continuous monitoring systems. There is none in Annex 1 and ISO14644 is for room classification only. Continuous – what, for example, does the word continuous mean? Monitoring – where should we locate the monitoring points and how many should there be? 5micron – what do we do if we see 5micron counts. How many are acceptable before we initiate and action limit 1 cubic metre – it is not clear as to whether we should try to sample a complete cubic meter during each manufacturing batch. Some aseptic manipulations are complete in a matter of minutes and it currently takes at least 20 minutes to capture 1cubic metre of air with a modern counter. Powder – are we really supposed to monitor for particles during a powder fill?
Scope & Aims of PHSS Special Interest Group Scope: – Cleanroom non-viable air particle monitoring – EU GMP Annex 1
Aims: – Collate best practice from Industry, Healthcare and regulatory bodies – Publish monograph :
Best Practice for Particle Monitoring in
Best Practice Document – the team AstraZeneca Bio Products Boehringer-Ingelheim Boots Contract Manufacturing Cardinal Health GlaxoSmithKline Hach Ultra Analytics Ipsen Biopharm Particle Measurement Techniques Wyeth MHRA Regulatory Inspectors (EMe A)
Best Practice Document Contents Changes to EU GMP Annex 1 – published 2008, ‘live’ March 2009 System Design Operations Maintenance and Cleaning Training Appendix A – Worked example Appendix B – Manifold and Remote Particle Monitoring Systems Appendix C – Examples of particle loss in transport tubing Appendix D – Isokinetic probes Appendix E – Validation and risk assessment standards
UK PHSS Best Practice monitoring Grade A areas counters.
monitored
continuously
using
dedicated
particle
Grade B areas (background for a Grade A) use dedicated particle counters. Other Grade B areas and Grade C areas may be monitored by manifold systems to check that they are under control. (No te: There are no limits for the ‘in operation’ state in Grade D areas.)
Corridors and change areas may be checked on a routine basis using portable particle counters or monitored using manifold systems. Enhanced monitoring should be provided in certain Grade C and D areas, for example in biologicals sites where low grade areas can potentially contribute a significant bioburden (to the point of sterility failure).
Appendix B – dedicated counter Grade A Vial Sterilizing Tunnel
Key Remote Counter Vacuum Tubing, Power & Data
Central Software System
Central Vacuum Pump
Appendix B – dedicated counter Grade A Vial Sterilizing Tunnel
0.5μ
0.5μ
Key Remote Counter
0.5μ 0.5μ
(Built-in Pump)
Power & Data Vacuum Tubing
Central Software
0.5μ
Appendix B – Manifold for Grade B & C Vial Sterilising Tunnel
Key Sample Probe Vacuum Tubing
Particle Controller Counter
Manifold
FDA ASEPTIC PROCESSING CGMP GUIDANCE After over 15 years, US FDA published on 27th. September 2002, a Concept Paper entitled “Sterile Drug Products produced by Aseptic Processing & and invited comments Subsequently issued as Draft GMP guidance in August 2003 and final CGMP in September 2004 New topics include guidance for personnel qualification, cleanroom classifications under dynamic conditions, environmental monitoring, isolators, blow-fill-seal systems Appendix 1 reiterates FDA’s view that isolators should not be located in unclassified rooms and suggests Class
FDA ASEPTIC PROCESSING CGMP GUIDANCE Air classification given in Table 1 of Buildings & Facilities only gives number of particles of 0.5 micron and larger per cft/cu.metre. Also dynamic state only. In this respect it differs from EU GMP as no mention is made of 5 micron particles • “Regular monitoring should be performed during each shift” • “Non-viable particulate monitoring with a remote counting system is generally less invasive than the use of portable particle counting units and provide the most comprehensive data” •
FDA ASEPTIC PROCESSING CGMP GUIDANCE • Air changes - For Class 100,000 (ISO Class 8) supporting rooms, at least 20 air changes per hours is typically acceptable, for higher cleanliness classes “significantly higher air change rates” • Air velocity: “air in critical areas should be supplied at a velocity sufficient to sweep particulate matter away from the filling/closing area and maintain laminarity. • A velocity of 90 to 100 ft/min +-20% is recommended
90 to 100 ft/min air velocity? The 90 to 100 fpm +/- 20% value should be a "guideline value" (in MCA terminology) or "informative" (in ISO terminology). • The magic of 90 fpm has been known to be a fallacy within the cleanroom industry for over 25 years. • This value is based on a simple calculation that a 5 um particle would stay airborne (settle less than 2 feet) over a distance of 20 feet in a horizontal flow cleanroom. • The true test is airflow pattern testing •
U.S.FDA ASEPTIC PROCESSING CGMP Differential pressure should be monitored continuously throughout each shift and frequently recorded “We recommend conducting non-viable particle monitoring with a remote counting system” Airflow velocities are measured 6 inches from the filter face or at a defined distance proximal to the work surface, for each HEPA filter Samples from Class 100 (ISO Class 5) environments should normally yield no microbiological contaminants
FDA GMP -WEAKNESSES Dynamic Classification Expected “ …… the final room or area classification should be derived from data generated under dynamic conditions”. Comments This is very difficult in practice, and facilities are normally classified under static conditions as per ISO 14644.Various factors outside the control of cleanroom contractors make classification in operational mode difficult such as gowning practice, microbial control, etc.
FDA GMP -WEAKNESSES Sterility Expectations “Air monitoring of critical areas should normally yield no microbiological contaminants” also “Samples from Class 100 environments should normally yield no microbiological contaminants”
Comments: Attaining a “sterile state” in an aseptic processing facility is impossible. Personnel are always present in manned cleanrooms performing various activities including microbial sampling. Detection of microorganisms occasionally is inevitable and need not be
AIR CHANGES Describing airflow in terms of air changes per hour is common for non-unidirectional flow rooms (ISO classes 6 through 9) and high-bay installations. Since the airflow in these rooms is non-uniform, attempting to directly measure the average air velocity is not feasible. The average velocity may be calculated, however, using volumetric measurements from the terminal filters. This velocity is then converted into an equivalent room air changes per hour (AC/H).
• It is worth noting that in the UK GMP ('Orange Guide') the room air change requirements have been removed in the latest edition.
EU Annex 1 vs. FDA Guideline EU Annex 1
FDA Guideline
Sizes monitored
5 micron
0.5 micron
Room Classes
Grades A, B, C, D
Critical = A
Grade B as surrounding Grade A
Controlled = C, D
0.5 micron
States to be At rest monitored In operation
In operation
FDA CGMP -- HEPA FILTER TESTING • HEPA filter integrity testing should be performed twice a year • DOP /PAO challenge and scanning with aerosol photometer is recommended (DOP not banned) • Concentration of poly-dispersed aerosol should be “appropriate for the accuracy of the photometer” (previously FDA had suggested 80 to 100 ug/L which was too high. Normally 20ug/L sufficient)
EN 1822 - European Standard for Filters
HEPA Filter efficiency tested at MPPS Leak Testing also at MPPS Efficiency as low as 85% rated as HEPA Particle Counter and CNC only, no photometers A suitable 0.1 micron sensitivity particle counter would also require a dilutor and the total cost would be around $ 20,000 i.e. double that of a photometer
