- Developments in Container Closure Integrity Testing of Lyophilised Product
- Development of Platform Processes for the Manufacture of Biopharmaceuticals
- Minimizing the risks of the value chain in the field of health
- Proposed specific amendments to Annex 1
- The quality and sterility of the finished product of a BFS process
- Creation of A3P BFS Common Interest Group?
- Fully Automated Particle Inspection in Blow Fill Seal Containers - A new approach
- Principles of automatic washing and common mistakes
- Four strategies to improve competitiveness in pharmaceutical and medical devices industries
- Management - Some Thoughts on Site Management and Leadership, Sharing Experience and Little Tricks ...
As announced in the previous issue, the IAG A3P Annex 1 proposed more general comments about 120 specific changes which are summarized below in 57 changes.
Addition: details of sterile products covered by Annex 1, adapting and validating the sterilization techniques to the product, the quality of these products also depends on the premises and equipment.
Addition: details are sterile products in the scope of Annex 1, validate sterilization methods and adapted to the product, quality of products aussi thesis related to premises and equipment.
AREAS CONTROLLED ATMOSPHERE M2
Annex / LD 1 3 points.
Correction: UDAF speed measurement filter near the terminal and not to the work plan
Addition: view UDAF with smoke tests and record.
The main changes concern the class A for unidirectional flow whose speed must be measured close to the terminal filter in accordance with ISO 14644 and that is recommended to view recorded by smoke tests. In closed systems turbulent air can be allowed and the critical area can be positive or negative pressure for containment.
CLEAN ROOMS M2
Annex 1 3 points.
Correction: UDAF airflow velocity taken close to the terminal filter and not at the working station
Addition: UDAF displays with smoke testing and video taken.
Hand Grade A areas in exchange for the unidirectional with the airflow speed based samples taken on filter close to the terminal selon ISO 14644 and visualised with smokes Recorded tests. In closed systems Could Be can turbulent air and the critical area Could Have Either overpressure or negative pressure in case of containment.
|CLASSIFICATION OF AREAS AND DEVICES CONTROLLED ATMOSPHERE |
Comment: no change to the particles ≥5 .mu.m potential carrier microorganisms
Addition: Add to particulate microbiological assessment qualification
M3: Annex / LD 1 4 points. Zones and controlled atmosphere devices should be classified for the particles according to EN / ISO 14644-1 and to evaluate the microorganisms in agreement with the ISO14698-1.
Change: Classification of areas preferably activity during simulated operations
M4: Annex / LD 1 7 point. The classification "in activity" can be demonstrated preferably during simulated operations since it is asked to reproduce the most unfavorable situations ...
|CLEAN ROOM CLEAN AIR AND DEVICE CLASSIFICATION|
Comment: no change for ≥5 microns particles since potential medium for microorganisms
Addition: Add to microbiological assessment particle classification
M3: Annex 1 4 points. Clean rooms and clean air devices shoulds be classified for particles in according with EN ISO 14644-1 and Evaluated for microorganisms in according with ISO 14698-1.
Change: "In operation" classification preferably Could Be Demonstrated During simulated operations
M4: Annex 1 7 points. "In operation" classification May be Demonstrated During preferably simulated operations as worst-case simulation is required for this.
|MONITORING AREAS AND DEVICES FOR CONTROLLED ATMOSPHERE|
M5: Annex / LD 1 8 points. Addition. The samples needed for monitoring are detailed in the number, frequency, location and updated in light of experience. It is noted that the sampling systems must not disturb the unidirectional air should avoid the possible loss of ≥5μm particles.
M6: Annex / LD 1 11 and 12 points. Checking up static systems of monitoring particulate and low sample volumes to rapidly detect any excursion, the link to a potential event and generating an alarm to operators.
M7: Annex / LD 1 13 points. Addition. 0 target class A ≥5.0 microns for particles, but monitoring ISO 14644-2 if intrinsic particles.
|CLEAN AIR AND CLEAN ROOM MONITORING DEVICE |
M5: Annex 1 8 points. Addition. More details on the required number of monitoring samples, frequencies, locations and regular review to update experience. Sampling system `shall not disturb UDAF and Avoid loss of ≥5 microns particles.
M6: Annex 1 11 and 12 points. Addition. The static particle counting system in place shoulds be verified and reliable sampling volumes to sample Quickly, to link a particle excursion to an actual event and to generate an alarm to operators.
M7: Annex 1 13 points. Addition. In Grade A target 0 ≥5.0 microns for particles, HOWEVER intrinsic particles in case of monitoring in according with ISO 14644-2.
Deletion: ... by methods such as ...
M8: Annex / LD 1 18 points. Addition: The means by culture to use elaborated and validated rapid methods are possible.
M9: Annex / LD 1 20 points. Addition: If exceeded
Deletion: ... using methods such as ....
M8: Annex 1 18 points. Addition: Methods based growth is rapid Indicated and validated methods Encouraged. Indications for sampling frequencies and timing for the delay entre sampling and incubation and the strategy for the definition of temperature and duration of incubation.
M9: Annex 1 20 points. Addition: For excursion investigation for root causes with implementation of CAPA and in Grade A impact on the batch release.
M10: Appendix 1 21 point to 25. Modification and Addition. The Insulators chapter is replaced by Technologies Barriers to include closed RABS operation and expand their definition, design recommendations, area classification, qualification, decontamination / sterilization, maintaining the integrity and maintenance, monitoring Environment and Material Transfer.
For monitoring of the environment: "A particulate and microbiological environmental monitoring plan must be set up on the basis of qualification data and a risk analysis: given the level of sterility assurance reinforced isolators / closed RABS, a microbiological surveillance program and reduced aseptic filling simulation can be considered on the basis of a sufficient and satisfactory history while a continuous particulate monitoring is still required in the critical area. "
M10: Annex to 1 21 25 point. Modification and Addition. The section is changed Isolators for Barrier Technologies Including closed RABS in operation. The section Gives details on definition, recommendations about the design, classification areas, qualification, sterilization or decontamination and maintenance of integrity, environmental monitoring and materials transfer.
For environmental monitoring: "An environmental monitoring program for particles and microorganisms based was documented risk analysis and data Obtained During qualification: due to the high level of sterility assurance in Isolators / closed RABS the microbiological monitoring program and the aseptic process simulation program is based Could Be Reduced Satisfactory Sufficient and historical data, the goal continuous particle monitoring is still required in the critical area. "
TECHNOLOGY FORMING / FILLING / SEALING (BFS) AND BOTTLE CLOSED
M11: Annex / LD 1 26 points. Modification and addition. BFS both technologies are specified, class sterile air shower A for the alternative process, assimilation to a closed system for the rotary process with validation of maintaining an air quality class A.
M12: Annex / LD 1 26 the point a. Addition. Adding technology closed bottle.
M13: Annex / LD 1 27 points. Addition. BFS recommendations for environmental monitoring in the filling point and close aseptic process simulation and strategy.
|BLOW / FILL / SEAL TECHNOLOGY AND TECHNOLOGY CLOSED VIAL|
M11: Annex 1 26 points. Modification and addition. The BFS 2 technologies are available with a Differentiated Grde A air shower for the alternative process and with consideration as a closed system for the rotary process with validation of the service of the Grade A air supply.
M12: Annex 1 26 the point a. Addition. Closed vials technology is added.
M13: Annex 1 27 points. Addition. For BFS recommendations for environmental monitoring at the filling point and around, strategy for aseptic process simulation.
|ASEPTIC PREPARATION IN CLOSED SYSTEM|
M14: Annex / LD 1 32 and 33 points. Modification and addition. The handling of sterile ingredients, solutions preparation, handling and filling of aseptically manufactured products must be a class A workstation in a local class B. When these operations are made entirely validated closed system (without open reading frames), a C or D class environment is suitable.
Addition to the glossary: Setting a closed system or process: a process step (or system) that uses work equipment in which the product or surfaces in contact with the product are not exposed to the work environment. Equipment used are never opened in the final after washing and sterilization work environment.
|ASEPTIC PREPARATION SYSTEM USING CLOSED|
M14: Annex 1 32 and 33 Point Modification and addition. Handling of sterile starting materials, preparation of solutions, handling and filling of aseptically Prepared products shoulds be done in a grade A environment with a grade B background. For operations using thesis only validated closed systems, a grade C or D background is acceptable.
Addition in the glossary: Definition of a closed system: process step (or system) manufacturing equipment using the product or product Within contacting surfaces are never exposed to the manufacturing environments. The equipment used is never open in the surrounding environment after-final washing and sterilization.
M15: Annex / LD 1 36 point. Addition. ... aseptic fabrications with direct human intervention in the absence of barrier systems.
M16: Annex / LD 1 37 points. Addition. Necessary training according to detailed activities, staff empowerment to enter the CAZ and dressing with periodic checking, regular verification of QA practices, training to minimize direct human intervention in class A.
M15: Annex 1 36 point. Addition. ... manufacturing aseptic processing with direct human interventions without any barrier technologies. Cancellation as far as possible.
M16: Annex 1 37 points. Addition. Training required for different activities and detailed, qualified staff for Reviews entering in clean areas for aseptic and clothing with periodic verification, periodic verification by QA behavior required of staff, training required to live minimize human intervention in Grade A.
M17: Annex / LD 1 46 points. Addition. The use of more and more frequent hydrogen peroxide on the joints of the walls and the
M18: Annex / LD 1 46 and 47 points. Addition. Any acute angle is not desirable in area C and D, or acceptable in A / B areas.
M19: Annex / LD 1 48 and 49 points. Addition. To avoid particulate and microbiological contamination clarification is given on false ceilings, technical areas above the ZAC, power supplies and other pipelines and piping feeding the BIA.
M20: Annex / LD 1 51 points. Addition. The different parts of the different sequences and changing rooms for undressing and dressing are described precisely in order to avoid the introduction of contaminants in the ZAC.
M21: Annex / LD 1 53 points. Addition. The various possibilities for the air supply and the pressure differences are discussed according to the operations to be performed.
M22: Annex / LD 1 54 points. Addition. Checking the ventilation pattern in initial and recurrent qualification is added here with the recommendation to make video recordings of the tests.
M23: Annex / LD 1 55 points. Addition. The importance of
M17: Annex 1 46 points. Addition. A periodic monitoring is recommended in case of frequent use of corrosive agents as hydrogen peroxide Such ble to damage walls and partitions and degrade etancheity premises.
M18: Annex 1 46 and 47 points. Addition. Any acute angle Neither is desirable in Grade C and D areas nor acceptable in Grade A and B areas.
M19: Annex 1 48 and 49 points. Addition. To prevent prevention particulate and microbiological contamination are more details for false ceilings Given, technical areas and cleanzones Above everything Regarding Necessary Any electric connections, pipes and ducts.
M20: Annex 1 51 points. Addition. The different parts of changing-rooms are for gowning Clearly Indicated as well as for de-gowning in order to Avoid introduction of contamination in clean areas.
M21: Annex 1 53 points. Addition. The different options Regarding air supplies and pressure differentials are Indicated DEPENDING on the manufacturing operations to perform.
M22: Annex 1 54 points. Addition. The air-flow patterns shoulds be verified and initial qualification During this shoulds be Recorded video.
M23: Annex 1 55 points. Addition. During recording critical operations of major pressure differences are particurlarly and shoulds be verified During batch release. Any OOS shoulds be Investigated and documented.
M24: Addition.Tout equipment coming into direct or indirect contact with the sterile pharmaceutical product must be sterilized beforehand and not only disinfected or decontaminated.
M25: Annex / LD 1 56 points. Addition. The output of the areas not classified products must be subject to a protection or validation to prevent reverse contamination areas of classes A, / B, or C.
M26: Annex / LD 1 59 points. Addition. To prevent
M27: Annex / LD 1 60 points. Addition. Recall the traçabilté of all maintenance activities.
M24: Additional item. Any equipment used directly with pharmaceutical product or indirect contacts must be sterilized and disinfected or THUS not only decontaminated.
M25: Annex 1 56 points. Addition. The exit of sterile pharmaceutical products in areas unclassifified shoulds be protected gold validated to Avoid Any retro-contamination of Grade A / B or C areas.
M26: Annex 1 59 points. Addition. To prevent prevention Any biofilm development, water distribution systems are detailed with indications it flows, pipes qualities, deadlegs, monitoring, recording and traceability of all critical
M27: Annex 1 60 points. Addition. Remind traceability of all Maintenance
M28: Annex / LD 1 61 and 62 points. Addition. The Program
M29: Annex / LD 1 63 points. Addition. During fumigation ZAC and RABS / isolators it is necessary to validate that the air handling system eliminates the agents used.
M28: Annex 1 61 and 62 points. Addition. The disinfection program of clean areas with validated Including sporicidal agents is detailed and the monitoring of ict efficacy is required. Particular cautions shoulds be taken for agents used grade A / B areas.
M29: Annex 1 63 points. Addition. Fumigation of clean areas and isolators / RABS shoulds include the validation of the air supply Ability to Eliminate the agents used.
M30: Annex / LD 1 64 and 65 points. Addition. Precautions to be taken at different stages of production should also help to reduce endotoxins. The manufacturing areas should be dedicated to drugs using live microorganisms but if the containment and decontamination of live microorganisms were validated using multi-product manufacturing areas can be justified in accordance with Annex 2 .
M31: Annex / LD 1 66 points to 70. Addition. The aseptic process simulation must be carried out for all aseptic process step not only for the final filling always with the same goal of zero contamination. It must take into account all interventions inherent in the process or corrective and the worst cases. Interventions authorized routine should be documented and simulated at the same frequency.
M32: Annex / LD 1 72 points. Addition. Treatment and water distribution facilities levy systems should be designed and operated so as not to be a source of rétrocontamination system. If applicable online control systems can be installed to reduce the interventions on the system.
M33: Annex / LD 1 73 points. Addition. Direct human interventions in the critical zone are prohibited and where they can not be avoided the arrangements to minimize the risks are indicated.
M34: Annex / LD 1 77 points. Addition. Flows accessories, clean containers and materials should not cross the flow of dirty materials.
M30: Annex 1 point 64 and 65. Addition. Precautions to minimize contamination and endotoxin should be taken ... Dedicated manufacturing zones for products using live micro-organisms. However, they may be justified in the context of 2.
M31: Annex 1 66 points to 70. Addition. Any aseptic process step shoulds be simulated with a growing medium with the target of zero Sami contaminated unit. All processes related shoulds be simulated and corrective interventions at the Sami frequency than in the routine process Including worst case situations. Operators Participate shoulds at least in one simulation per year. In case of contaminated unit (s) the interpretation and CAPA shoulds be based on the investigation results.
M32: Annex 1 72 points. Addition. Sampling systems shoulds not be a source of retro-contamination of the water system and automatic on-line control systems are Encouraged to Reduce Direct interventions.
M33: Annex 1 73 points. Addition. Direct human interventions in the critical areas shoulds be Avoided or the operators movements shoulds be minimized by dedicating em to specific areas.
M34: Annex 1 77 points. Addition. Flows of clean components, materials and equipment shoulds never crossed Those of dirty ones.
|STERILE COMPONENTS READY FOR USE|
M35: Annex / LD 1 78 points. Accessories, containers and sterile equipment ready for use in long life must have a means to verify the maintenance of sterility during the implementation, such as the maintenance of the integrity of a vacuum packaging.
M36: Annex / LD 1 79 points. The storage of the products before their final sterilization or sterile filtration must be as short as possible, constructed to protect the environment of product (eg pressure, nitrogen sweep) and its duration must be validated.
M37: Annex / LD 1 80 points. Bioburden prior to sterile filtration should not be greater than 10 CFU for 100ml and therefore carried out on at least 100ml and before terminal sterilization 10 CFU per pharmaceutical unit.
M38: Annex / LD 1 81 points. In the case of a multi-pack containing substances or articles sterilized and intended to be removed in several stages when transferring in a controlled atmosphere zone, it is necessary to take into account the need to create a partial vacuum in the first package .
|READY-TO-USE STERILE COMPONENTS|
M35: Annex 1 78 points. Sterile components, containers and equipment with a shelf life as short as possible, not shoulds-have a mean to verify at the point of use of the integrity Each THUS the packaging and sterility, Such As a packaging under vacuum.
M36: Annex 1 79 points. The storage of products before sterilization or sterile filtration must be minimized and the product protected from environment (overpressure, sterile nitrogen). This time duration must be validated.
M37: Annex 1 80 points. The sterile filtration bioburden before shoulds be NMT 10 CFU / ml Performed with 100 100 ml at least, and for terminal sterilization NMT 10 CFU per pharmaceutical unit.
M38: Annex 1 81 points. For multiple layers packaging unwrapped During different transfer steps, consideration shoulds be taken que le first layer shoulds be wrapped under vacuum.
M39: Annex / LD 1 83 points. Addition. Reference to PhEur decision tree to adopt a method of sterilization which validation must be checked at least annually.
M40: Annex / LD 1 84 points. Addition. The validity of the sterilization process must be monitored at specified intervals, at least annually, and after each major modification to the equipment and product to be sterilized or equipment. In addition, a periodic review of sterilization equipment will be made at specified intervals, minimally every 3 years. The results, reported in the validation dossier, will ensure the non-diversion of critical parameters used in sterilization.
M41: Annex / LD 1 86 points. The use of part charges is allowed if their performance qualifications demonstrate not significantly different test reproducibility than the full charge.
M42: Annex / LD 1 87 points. The use of biological indicators is an additional means of control that does not replace the control of physical sterilization parameters.
Sterilization by heat
M44: Annex / LD 1 92 points. Replace "measure time
M46: Annex / LD 1 96 points. Title and non-condensable gas rate must be determined by the type of steam exhibits.
M49: Annex / LD 1 99 points. A qualification is added performances (QP) must be carried out to establish the correlation between the treatment dose limits and those of the control dose.
M39: Annex 1 83 points. Addition. The choice of sterilization method shoulds Refer to the Ph Eur decision tree and the validation Performed Annually at least.
M40: Appendix 1 84 points. The validity of the process shoulds be verified at scheduled intervals, at least Annually, and whenever will-have-been significant changes made to the equipment. Moreover a periodical review of sterilization equipment shoulds be Performed at least every 3 years. Records Kept shoulds be in the results of the validation report in order to verify the lack of adverse trends in critical sterilization parameters.
M41: Annex 1 86 points. Partial loads are authorized When Demonstrated performance-have qualifications similar reproducible results than for full loads.
M42: Appendix 1 87 points. Utilization of biological indicators shoulds be regarded as a supplementary control method qui can not replace the physical sterilization parameters.
Sterilization by heat
M44: Annex 1 92 points. Replace measurement of the sterilization-time period by measurement of the hold time bearing Ensuring sterilization.
M46: Annex 1 96 points. The title and the amount of non-condensable gases shoulds Be Determined DEPENDING on the products exposed to steam.
Sterilisation by radiation
M49: Annex 1 99 points. Addition. A performance is an added qualification shoulds be done to correlate treatment dose limits to control dose limits.
Change: "To be filtered" replaces "can be filtered" for sterilizable by filtration.
M50: Annex / LD 1 110 point. ... solutions or liquids should, where possible, be filtered on a filter ... otherwise it must be justified ...
Change: integrity check filters before possible use before sterilization.
M51: Annex / LD 1 113 point. The integrity of sterilized filters ... under pressure. Pre-use testing should not compromise the sterility of the filter or filtration system. If this is the case, this control can be performed before the sterilization step of the filter, the validation of which must demonstrate that it does not risk damaging the filter. The duration…
Change: must be filtered INSTEAD of can be filtered for reliable products to be Sterilised by filtration
M50: Annex 1 110 point. ... gold solutions must be filtered when possible through a sterile filter ..., otherwise this should be justified ...
Change: filter integrity test before use if possible, before sterilization.
M51: Annex 1 113 point. The integrity of the sterilized filter ... or pressure hold test. This verification should not be compromised by the filtration system. In this case this verification can be performed before sterilization. The time taken ...
|FINAL STEPS OF MANUFACTURING|
Addition: integrity check to 100% recommended, where possible.
M52: Annex / LD 1 117 point. For other containers the integrity test at 100% is recommended, where possible, otherwise the integrity test must be performed on the basis of a sampling ...
Addition: clipping added to crimping.
M53: Annex / LD 1 118 points. The ability to use a clipping capsules is added to crimping.
Addition: when to 100% integrity check is not possible.
M54: Annex / LD 1 120 point. ... In the latter case and if an integrity check at 100% is not possible, the containers must be protected ...
Addition: maintaining the vacuum checked 100%.
M55: Annex / LD 1 123 point. For vacuum sealed containers, the vacuum hold must be checked at 100% ...
Change: mirage by operators in the conditions of the European Pharmacopoeia.
Correction: "Devices" instead of "glasses".
Addition: apparatus controlled for its ability to detect non-defective units for each lot.
M56: Annex / LD 1 124 point. When this control is performed visually, it must be done under the conditions of the European Pharmacopoeia by qualified operators. Operators ... with their correcting devices ... When using other methods, the process must be validated and the proper functioning of the equipment in its ability to detect non-conforming units must be checked for each batch.
|FINISHING OF STERILE PRODUCTS|
Addition: 100% integrity testing recommended, where applicable`.
M52: Annex 1 117 point. For other containers 100% integrity test is recommended, where applicable, otherwise samples should be checked ....
Addition: capping added to crimping.
M53: Annex1 118 point. ... not fully integral until the cap has been crimped or capped into place on the stoppered vial. Crimping or capping of the cap should therefore ...
Addition: When 100% integrity testing is not feasible.
M54: Annex 1 120 point. ... Where it is approached when 100% integrity test is not possible, vials should be protected ...
Addition: Maintenance of vacuum 100% tested.
M55: Annex 1 123 point. Containers sealed under vacuum should be 100% tested for maintenance of ...
Change: visual inspection done under European Pharmacopoeia requirements.
Correction: "Corrective Devices" INSTEAD of "spectacles"
Addition: ... equipment checked for its ability to detect any non-conforming unit for each batch.
M56: Annex 1 124 point. ... When inspection is done visually, this should be done under the European Pharmacopoeia. Operators doing ... with corrective devices ... the performance of the equipment checked at intervals for its ability to detect any non-conforming unit for each batch.
QUALITY CONTROL M57
Addition: Rapid Microbiological Methods (MMR) validated
Addition: MMR required for product released before the results of sterility testing where applicable.
Annex / LD 1 125 points. The use of validated rapid microbiological methods is recommended. For sterile products short life used prior knowledge of the result of sterility testing by culture, the use of rapid microbiological method validated is required if applicable for these products.
|QUALITY CONTROL M57|
Correction: Contributing to sterility assurance INSTEAD of by qui sterility is assured.
Addition: Validated use of Rapid Microbiological Methods (RMM) Encouraged.
Addition: MMR mandatory for products released before the sterility test result.
Annex 1 125 point. The implementation of rapid microbiological methods is encouraged. For sterile products with a short shelf life, the results of a sterile test result, the implementation of a validated rapid microbiological method is mandatory if applicable
we should, with guidance on the new Annex 1 at the round table of the annual meeting of the PHSS (Healthcare Pharmaceutical Science Society) in London on September 11 organized on this subject with the participation of the inspector group leader EMA / PICS Andrew Hopkins and major contributory associations whose A3P. Following the publication of the draft Annex 1 2015 expected before the end, the ICG will meet to form working groups to formulate remarks A3P, possibly as a result of consultation with members. A progress update will be made at the upcoming International Congress A3P the 19 November.