GMP Trends: Contamination control according to Annex I effective from 2009

Transcription

1 ETIF 2008 Costa Salguero Centre - Buenos Aires - Argentina 24 October 2008 GMP Trends: Contamination control according to Annex I effective from 2009 Revision of Annex 1, 14/02/2008 Giovanni Bini

2 Contents Revision History Introduction Cleanrooms Classification Cleanrooms Routine Monitoring Blow/fill/seal Media Fill Bioburden Capping of vials Conclusions 2

3 Revisions History EU GMP Annex 1 Manufacture of Sterile Medicinal Products (1997) EU GMP Annex 1 Manufacture of Sterile Medicinal Products Revision September 2003 EU GMP Annex 1 Manufacture of Sterile Medicinal Products Revision 14 February 2008 Aim of the revision: Keep pace with technological change; Solve some interpretation problems Harmonize with the ISO guidelines and FDA regulations. 3

4 Introduction The Annex 1 of EC Guide to GMP, Manufacture of Sterile Medicinal Products, has been recently reviewed (February 2008) concerning on the following topics: Classification of Cleanrooms; Media Fill execution method; Advices concerning bioburden for sterilization loads; Advices concerning capping of vials. 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,

5 Introduction 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 Volume 4, EU GMP, Annex 1 Manufacture of Sterile Medicinal Products February 2008 Production with final sterilization Aseptic production Where possible, heat sterilization is the method of choice 5

6 Introduction For the manufacture of sterile medicinal products 4 cleanroom cleanliness grades can be distinguished: Grade A: The local zone for high risk operations. Laminar air flow systems should provide a homogeneous airspeed in a range of 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. 6

7 Introduction Examples of operations to be carried out in the various grades: Grade A C D Examples of operations for terminally sterilised products. Filling of products, when unusually at risk Preparation of solutions, when unusually at risk. Filling of products Preparation of solution and components for subsequent filling Grade A C D Examples of operations for aseptic preparations. Aseptic preparation and filling Preparation of solution to be filtered Handling of components after washing 7

8 Cleanrooms Classification The requirements for classification are clearly defined Initial Classification Routinary monitoring The following is applied to Cleanrooms Clean Air Devices (hoods, LAF, isolator, RABS, ) 8

9 Cleanrooms Classification Clean rooms and clean air devices should be classified in accordance with EN ISO ; the table for particles limits has (almost) been harmonized with it Maximum permitted number of particles per m 3 equal to or greater than the tabulated size At rest In operation Grade 0.5µm 5.0 µm 0.5µm 5.0 µm A B C D Not detect Not detect For classification purposes EN/ISO 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 9

10 Cleanrooms Classification ISO 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 Class Class Class Class Class Class Class Class N. Sampling points N = (m 2 ) Sampling Volume Vs = 20 (m 3 ) Cmax A I.e. a sampling volume adequate to capture 20 particle at the upper limit of the class. 10

11 Cleanrooms Classification Particle size 5.0 µm 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/m 3 for grade B at rest. Despite that, the limit for such particles for grade A, formerly of 1 part/m 3 changed to 20 part/m 3 : 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. was 11

12 Cleanrooms Classification Comparison between particles limits (n. part./m 3 ) Annex 1 (2003) vs. Annex 1 (2008) Grade A B C D Particles 0.5µm (3.500) (3.500) ( ) ( ) at rest Particles 5µm 20 (1) 29 (1) (2.000) (20.000) Particles 0.5µm (3.500) ( ) ( ) No defined in operation Particles 5µm 20 (1) (2.000) (20.000) No defined (limits set in 2003 revision of Annex 1 are between brackets) 12

13 Cleanrooms Classification Sampling Volume 5. For classification purposes in Grade A zones, a minimum sample volume of 1m 3 should be taken per sample location. 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 formula was applied to 0,5 μm particles (0,1 ft 3 could be enough, typically 1 ft 3 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 m 3 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 m 3 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 m 3 sampling volume should be taken for sample location. 13

14 Cleanrooms Classification Correspondence with ISO 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 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. 14

15 Cleanrooms Classification Correspondence with ISO 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 m 3 ; it seems logical to interpret this requirement so as to use a sample volume of 1 m 3 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 , nothing prevents you from taking a typical sample volume of 1 ft 3 for "sampling location". 15

16 Cleanrooms Classification 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 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; 16

17 Cleanrooms Classification 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 m 3 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 17

18 Cleanrooms Routine Monitoring 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 minutes. 18

19 Cleanrooms Routine Monitoring 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. 19

20 Cleanrooms Routine Monitoring 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 Recommended limits for microbial contamination (a) Grade Air sample cfu/m 3 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 C D

21 Blow/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-inplace; 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. 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. 21

22 Media 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. 22

23 Media Fill 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. 23

24 Media Fill 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. Requirements concerning Media Fill have been harmonized with FDA. 24

25 Bioburden 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. 25

26 Capping 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 26

27 Capping of vials 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 Partially stoppered freeze drying vials should be maintained under Grade A conditions at all times until the stopper is fully inserted. 27

28 Capping of vials 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 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 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. 28

29 Capping of vials 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 Aair 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 Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation. 29

30 Capping of vials 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 (!!!) 30

31 Capping of vials 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. Note: capping machine should be separated from filling machine, in order to avoid contamination in the filling zone 31

32 Capping of vials 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 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. 32

33 Conclusions 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. 33

34 Revisione Annex 1 Risorse in rete Annex 1, revision 2008 Comparison between old and new Annex 1

35 Thank you for your kind attention