1. Introduction
The purpose of this document is to provide manufacturers of pharmaceutical preparations with guidance on the validation of aseptic manufacturing processes in accordance with Division 2 (Part C - Good Manufacturing Practices) of the Food and Drug Regulations and acceptable to the Health Products and Food Branch Inspectorate.
Sterile products can be divided into two broad categories according to their method of production, ie those which are sterilized after being placed in their hermetically closed final container ("sterilized after conditioning" products) and those for which the sterilization stage takes place before packing the bulk product. In the latter case, all subsequent treatment (usually distribution and sealing) must be done aseptically to prevent contamination of the sterilized product.
It has been established that aseptic processes play an important role in the sterilization of formulations that can not be sterilized after conditioning. However, post-conditioning sterilization, particularly wet heat processes, is considered the method of choice for the manufacture of sterile products as it provides higher assurance of sterility. Manufacturers who decide to make a sterile product without sterilization after packaging should be prepared to justify their decision and prove that their product can not be sterilized in this way, even through less rigorous autoclaving cycles tailored to the patient's needs. microbial load of the batch to be sterilized (approach of the probability of survival).
The two most common pharmaceutical applications of aseptic processes are a) the distribution of liquid products after sterilization by filtration, and b) the distribution of previously sterilized bulk powder products. Both of these processes are covered in this guide. Finally, the last section of the guide provides an overview of the documentation required to provide acceptable evidence that a given process has been carefully evaluated and adequately controlled.
It is assumed that the manufacturing and control activities are conducted at all times according to the principles of Good Manufacturing Practices, both generally and with respect to aspects specific to the manufacture of sterile products.
The steps recommended in this guide can be summarized as follows:
As a prerequisite, all studies should be conducted according to a pre-established detailed PROTOCOL (or series of protocols), which itself is subject to official change control measures. (See Section 3)Employees conducting the studies, as well as those who apply the process under study, should have adequate TRAINING and QUALIFICATION and be able to perform the tasks assigned to them. (See Section 4)All data obtained in the course of the studies should be formally EXAMINED and CERTIFIED, against pre-determined criteria. (See Section 5)The appropriate FACILITIES, EQUIPMENT, INSTRUMENTS and TEST METHODS should be available. (See Section 6)WHITE ROOMS should be available, ensuring a suitable environment both "local" and "general". The certainty that the cleanroom environment meets the specifications should be obtained during initial commissioning ("Qualification") and thereafter through the implementation of a program of periodic audits, in-process control and monitoring. (See Section 7)All equipment assigned to the treatment should be properly INSTALLED, QUALIFIED and MAINTAINED. (See Section 8)When the above points have been satisfactorily resolved, the aseptic process can be validated by means of "MIDDLE DISTRIBUTION" (or "PROCESS SIMULATION") studies. (See sections 9 and 10)The process should be REVALIDED at intervals. (See Section 11)There should be detailed DOCUMENTS that define, support and record the overall validation process. (See Section 12)
Although this guide only concerns the validation of ASEPTIC PROCESSES, it is crucial for the success of this type of process that the product, materials, components, etc., that are handled or treated aseptically (eg, solutions or bulk powders, containers and closures) and any equipment, container or surface (eg storage tank, piping, filler) that may come into contact with sterilized products or materials have themselves been previously sterilized validated and adequate processes. In any aseptic dispensing process, it is of course essential to ensure the integrity of the container and the closure. Supporting evidence should be provided in the general documentation of validation (see section 12).
2. Validation - general aspects and terminology
2.1 In the context of this guide, process validation means :
the steps taken to demonstrate that a process will consistently, with a high degree of certainty, produce the desired and intended results and provide the documented evidence.
2.2 Before the validation of a process begins, there must be what may be called an essential phase of prevalidation . This, in addition to the considerations relating to the specifications, the design and the purchase of the equipment, must pay attention to the qualification of the equipment .
2.3 The qualification of the equipment consists of two main phases:
2.3.1 the qualification of the installation , ie demonstration and certification that an item of equipment is properly installed, provided with all necessary services, accessories and instruments, and that it can operate according to its basic design parameters
2.3.2 operational qualification , ie demonstration that the equipment will operate on a regular basis within pre-defined limits, according to its specifications and installation.
2.4 It is not necessary to consider these different phases as "watertight" compartments. Divisions have been defined to facilitate discussion. In practice, there is likely to be overlap or clustering of the various components of validation and qualification. In addition, there are fairly large variations in terms and concepts. Thus, some regard "qualification" and "validation" as two distinct but related activities. Others use the term "validation" to encompass all prevalidation and qualification activities PLUS process validation.
The links between these various phases can be summarized as follows:Purchase design specificationsQualification of the equipmentQualification of the processQualification of the installationOperational QualificationSometimes called previdationGlobal validation process
2.5 Validation is also considered to include three possible aspects or strategies: prospectivevalidation, concomitant validation, and retrospective validation .
2.5.1 Prospective validation applies to new processes and equipment, includes the conduct and evaluation of studies, and results in confirmation of the entire process and equipment prior to the commencement of regular production .
2.5.2 Concurrent validation applies to existing processes and equipment. It consists of studies conducted during ordinary production and can only be suitable for processes whose manufacturing history and test results indicate a sustained quality of production.
2.5.3 Retrospective validation applies to existing processes and equipment and is based on historical data only. Unless sufficiently detailed treatment and control records are available, this type of study is unlikely to be feasible or acceptable. For example, it would be necessary to establish that the process has not been modified or that the equipment operates under the same conditions of construction and performance as those documented in the records. Maintenance records and process change documentation would be required to support any such statement. In addition, failure frequency as well as rejected and / or retired product files should be carefully examined for signs of process variability. Manufacturing, maintenance, verification and calibration data should all demonstrate uniformity, consistency and continuity of the process.
2.5.4 Conclusion on terms used in validation . While there is considerable variation in the understanding and use of the terms discussed above, there is general agreement that the crucial concepts of validation are:
the process as a whole is understoodthe specifications and the design of the equipment are adequatethe equipment is properly installed and maintained and is obviously operating according to its specifications and designthe process is validated to ensure that it gives the desired and expected result.
3. Development and control of the protocol
3.1 Each step of the validation of the overall process should take place according to a protocol (or series of protocols) written, detailed, pre-established and officially approved.
3.2 Prior to the commencement of studies, change control procedures should be established, in writing, to prevent unauthorized changes to the process itself or to the study protocol, and to limit changes at any stage process until all relevant data has been evaluated.
3.3 Protocols should bear a title, a date and a unique identification or reference number. They should also be officially authorized or approved by those with the authority and authority to do so.
3.4 Protocols should specify the following in detail:
3.4.1 Objectives and scope of the study, that is to say a clear definition of the purpose.
3.4.2 Clear and precise definition of the process, equipment, system or subsystem to be studied, as well as the operating characteristics.
3.4.3 Installation and qualification requirements for new equipment.
3.4.4 Upgrade Requirements for Existing Equipment, Rationale for Changes, and Statement of Qualification Requirements.
3.4.5 Statement describing point by point the steps to be followed in carrying out the study.
3.4.6 Assignment of responsibility for conducting the study.
3.4.7 Specification of all test methods to be used, and specification of equipment and materials to be used.
3.4.8 Requirements for equipment calibration for testing.
3.4.9 References to the relevant Standard Operating Procedures (SOPs).
3.4.10 Requirements for the content and presentation of the study report.
3.4.11 Criteria for acceptance of the study.
3.4.12 Personnel responsible for evaluating and certifying each stage of the study, and this step as a whole, against pre-established acceptance criteria.
4. Staff
As with all validation studies, documents attesting to the experience and training of the personnel participating in the studies should be retained. However, employees performing aseptic processing (both during a validation study and as part of routine operations) can and do have such an important effect on the quality of the final product that it is appropriate and necessary to consider these two aspects of staff participation.
4.1 Properly qualified employees should ensure that the protocol and test methods are based on sound scientific principles and that studies are properly evaluated and certified.
4.2 All personnel conducting the tests should be trained and experienced in the use of instruments, measuring devices and materials used.
4.3 Technical and maintenance personnel should be trained and competent to operate and maintain the machinery, equipment and air control systems used.
4.4 Although modern automated techniques and protective measures may reduce the risk of contamination, the importance of the "human factor" in all aseptic processing processes can not be overstated. For the results of a validation study to be valid, it is essential to have the greatest possible control over the risk represented by a variable as random as this human factor, in this case the operator. In other words, measures must be taken to reduce risk and minimize variability.
4.5 This means that any operator who participates in the aseptic process that is the subject of the validation study should adopt the same techniques, rules of discipline and hygiene standards, as well as the same clothing and behavior as during the manufacturing process. usual. The opposite is also true: if the operator does not behave in the same way during the usual process and during the validation study, the conclusions drawn from it will be invalid.
4.6 It is therefore vital that all aseptic process personnel be trained in GMPs and relevant microbiology elements and fully understand the concepts and principles. Employees must understand the importance of personal hygiene and cleanliness and be well aware of the risks that can result from product contamination.
4.7 Operators should be provided with clean room clothing and know how to use it properly. The type of clothing and how to wear them, as well as the "surgical brushing" should be established in written protocols, which operators can consult, preferably in the locker room. The standards for clothing and how to wear them should be the same in regular operations and validation tests.
4.8 The number of employees present during the validation tests should be the same as the maximum number of employees allowed to work in the clean room during regular production.
4.9 At all times, operators should be encouraged to report infections, open wounds, or any other condition that may result in the excretion of an abnormal number of particles or microorganisms. As is the case for manufacturing, no person with any of the above signs should be in a clean room during validation testing.
4.10 As with regular production, microbiological monitoring should be conducted by taking samples of gloves, gowns and masks from cleanroom operators participating in the validation study.
4.11 The usual process documentation should specify and record the number and type of operator interventions allowed during processing, and the circumstances in which they occur. A similar set of interventions should take place during the validation study. Relevant details should be provided in the general documentation of the validation process (see section 12).
Note: As mentioned in the introduction, it is assumed that all regular manufacturing and control operations are conducted in accordance with Good Manufacturing Practices, including the requirement that all employees have the training and competence to perform the tasks assigned to them.
5. Review of data and registration of the study
5.1 All information or results obtained in the course of the study should be evaluated by qualified persons against the criteria of the protocol and declared compliant or non-compliant. Written evidence in support of the evaluation and conclusions should be available.
5.1.1 These assessments should be conducted as the information becomes available.
5.1.2 If the evaluation reveals that the protocol criteria have not been met, it must be concluded that the results are not acceptable and the reasons for this failure should be investigated and documented.
5.1.3 Any breach of the methods described in the protocol must be considered as invalidating the study itself; if so, its impact on the study must be carefully evaluated.
5.1.4 The final approval of the validation study should specify the pre-established acceptance criteria against which the results were assessed.
6. Laboratory
6.1 All laboratory tests (including physical, chemical and microbiological) should be performed by a competent, well-equipped laboratory with well-trained and qualified personnel to perform the tasks assigned to them.
6.2 There should be a written, detailed and authorized procedure describing the relevant methods validated for all laboratory tests performed during the study. This procedure should be referenced in the study protocol.
6.3 If external laboratories are used, there should be a system in place to determine whether these laboratories have the necessary skills to perform the required tests. Compliance with this requirement should be documented in the protocol.
6.4 All measuring, recording or indicating devices used in the studies should be adequate in terms of range of values, accuracy, reproducibility, etc. They must be calibrated in accordance with pre-determined written methods prior to commencement of validation studies.
6.5 A record of each calibration should be kept and kept with general validation documentation.
6.6 In order for the conclusions of qualification or validation studies to remain valid for ordinary production, all control and recording instruments must be submitted to a written maintenance and calibration program.
7. Environmental Considerations: Standards, Qualification and Monitoring for the Clean Room
7.1 Although products, materials, containers, components, closures, etc. may, prior to sterilization, be handled or treated in a clean room environment with less stringent specifications (eg Class C), after sterilization, all aseptic processing operations should be performed under Class A protection ("Workstation"), within a Class B clean room environment. However, if specialized, automated or barrier-type techniques are used to provide localized protection, a less stringent standard may be used. acceptable to the surrounding environment, provided that process validation studies demonstrate an acceptable degree of certainty for sterility. (Classes A, B and C are defined in the "Basic Environmental Standards for the Manufacture of Sterile Products" table in the Sterile Products section of the current version of the Good Manufacturing Practices Guidelines.
7.2 In order for the results of validation studies to be extrapolated to regular production, these studies must be carried out exactly under the same environmental conditions that are used or planned to be used in regular production.
7.3 It can be considered that the confirmation and certification of the conformity of the room and workstations to the specified environmental standard is part of the qualification phase of the facilities. For this purpose, the following basic operations should be performed during the initial commissioning (or "qualification") of a new clean room:
Verification of the integrity of the air filters in the roomdetermination of the rate of flow of air on the surface of each air intake filterair exchange rate of the roomparticle count in the air of the roomdifference in air pressure and air flow pattern in the roomlighting, heating, humiditychecking the efficiency of air filters at workstationsdetermination of airflow velocity at the surface of air filters at workstationsparticle counting in workstation areas
7.4 After initial commissioning, a regular audit program should be adopted, including the following:
7.4.1 Verification of room air filters and workstations : at least once a year, unless the results of the in-process check indicate the need for more frequent or additional checks.
7.4.2 Determination of airflow rate and room air change rate : at least twice a year.
7.4.3 Particulate matter determination: to be determined as part of the regular in-process inspection, an official attestation being provided by a competent specialized body three times a year.
7.5 Differences in room air pressure should be monitored permanently.
7.6 Walls, floors, workstations and surfaces should generally be subject to a pre-established cleaning and disinfection program.
7.7 To ensure that products remain, during manufacturing, within the quality parameters established as part of the overall validation process, it is necessary to design and implement a control and monitoring program during manufacture. Similarly, to ensure that validation studies are conducted under conditions comparable to those of the regular process, a similar control and monitoring program should be applied during validation testing.
7.8 In-process control and monitoring can be considered in three ways:
Particles in the surrounding environmentMicrobiological monitoringChecking the integrity of the filters
7.9 Depending on the type of manufacturing process, the following microbiological monitoring and control methods should be considered:
Verification of the microbial load in the main solution, before sterilization by filtration.Exposure of "indicator boxes" (Petri dishes filled with nutrient agar) to critical areas of the clean room and workstations subject to verification.Use of air sampling devices to determine the number of viable organisms per cubic meter (or cubic foot) of air in the room, and at workstations.Use of contact boxes or swabs to check microbiological quality of surfaces.
7.10 In order to verify that the air in the room and the workstations conforms to the specifications, the monitoring, including the counting, of the particles in the surrounding environment should be carried out using the appropriate apparatus.
7.11 Verification of the integrity of the filters used to sterilize the product is critical in the manufacture of sterile products. If the product can not be sterilized in its final container, the solutions or liquids can be filtered through a sterilized filter with a normal porosity of 0.22 micron (or less) in a previously sterilized container. The integrity of the sterilizing filter should be verified prior to use and confirmed immediately after use by an appropriate method such as bubble point, diffusion test, or pressure maintenance test.
7.12 In-process inspection and monitoring should be carried out according to a pre-established written program describing the precise limits and standards of the tests; all results are formally reported and assessed against these limits. This requirement applies as much to validation studies as to the regular process of manufacture.
8. Qualification and maintenance of equipment
8.1 A wide variety of mechanical devices can be used for various aseptic processes. Before the start of a validation study, it is necessary that all the pieces of equipment are properly qualified, both in terms of installation and operation (see sections 2.2 and following), and that qualification is attested. The detailed description of the installation and operating requirements for all equipment is clearly outside the scope of this guide. However, the essential requirements are:
confirmation that the equipment was built to specificationsconfirmation that the equipment has been properly installed and provided with all necessary services, ancillary equipment and instruments, in working orderconfirmation that the equipment can operate smoothly, within the pre-determined limits, over its defined operating range.
8.2 There must be confirmation that treatment equipment is qualified before any subsequent study can be considered valid.
8.3 In order for the results of the validation study to remain valid for regular manufacturing, a complete regular maintenance program should be developed detailing each activity and its frequency, in real time, in machine time or on any other time base. The time base chosen should be clearly defined for each operation.
8.4 Unless such a program is developed and implemented, and manufacturing equipment and ancillary instruments remain in the same condition as validation studies, any assurance provided by such studies may be compromised.
9. Environmental Distribution Studies (In Solution Products)
9.1 In the technique of "medium distribution" or "distribution of broth", a liquid microbial growth medium is prepared which is distributed by simulating a normal manufacturing operation. The nutrient medium is processed and handled in a manner that best simulates the "normal" manufacturing process, including exposure to contamination risks (from operators, the surrounding environment, equipment and surfaces) . The sealed medium containers thus obtained are then incubated under pre-established conditions and then examined; evidence of microbial growth is sought, and these results provide an indication of the level of contaminated units. This process is summarized in Figure 1.
Figure 1: Flowchart of the distribution of liquid medium in flasks.
NOTES:
Different types of containers will require different methods of sterilization. For example, the sterilization of glass bottles will probably be done by dry heat and that of plastic bottles, by irradiation or exposure to ethylene oxide.All other components, such as teats or droppers, should also be pre-sterilized by an appropriate validated method.The flowchart of the distribution of medium in ampoules will be similar to the flowchart above, with no plug and capsule operations, etc.
9.2 It is important to realize that the medium distribution test is often, among other things, a verification of the aseptic techniques of the operator. In this situation, the operators can hardly ignore the fact that the distribution is made with nutrient medium and that they themselves are, to a certain extent, "subjected to a test". Therefore, it is possible that they take more precautions than usual, which prevents accurate simulation of the usual process. Every effort should be made to ensure that operators behave in the usual way during the distribution of the environment and, conversely (which may be important), that they do not derogate from the high standards adopted during the studies. validation during regular operations.
9.3 Another difficulty to note is the risk of contamination of laboratories and equipment by the nutrient medium. If the process is well controlled and the distribution of media is rapidly followed by cleaning and disinfection, and (if necessary) sterilization of the equipment, there should be no contamination. Nevertheless, it is important to recognize this risk and act accordingly.
9.4 It must also be emphasized that the distribution of a nutrient medium solution in itself is not an acceptable validation of aseptic processes. The entire manufacturing cycle must be simulated, from the distribution and reconstitution of the powdered medium using normal manufacturing conditions, to distribution and sealing. The operators (and the number of operators), the number and type of filtrations, etc. should be the same as under normal conditions, as well as retention times in mixing vessels, temporary storage tanks, etc. General activity should be at a normal level, and no "special" precautions should be taken to ensure that the test will be successful. In fact, if there is to be a variation from the normal, it can only be in the direction of larger, not least, difficulties to be overcome microbiologically.
9.5 Before a valid validation of the environmental media is undertaken, all necessary equipment qualification and instrument calibration measures must be completed, as well as the appropriate certification (see, for example, sections 6 and 8). It should also be confirmed and certified that clean rooms for all stages of treatment meet environmental standards. (See Section 8)
9.6 Normal in-process control and monitoring operations (see Section 8) should be performed during the environmental distribution tests.
9.7 The liquid nutrient medium used should meet the criteria below.
Selectivity:
The medium should have low selectivity, that is to say allow the growth of the widest possible range of microorganisms likely to be encountered.Limpidity:
Once reconstituted, the medium should be clear to allow any signs of growth to be observed after incubation.Filtration:
When the simulated process comprises a filtration step, the liquid medium should be able to be filtered through a microbial retention filter of the same type and quality that will be used to filter the true product. The soy casein lysate medium, sometimes referred to as "tryptic soy broth" is perhaps the most commonly used liquid medium. However, other formulations (e.g., yeast tryptone glucose extract, brain-heart perfusion medium, etc.) may also be employed, provided they meet the above-mentioned criteria.
9.8 The liquid medium should be sterilized either by filtration (if this step is normally part of the simulated operation) or by pre-sterilization with heat and cooling to room temperature before proceeding.
9.9 The number of units to be filled per cycle should be high enough to detect with high probability a low level of microbial contamination. For example, in order to be able to detect with a 95% confidence level a contamination rate of one per thousand filled units (0.1%) with a sterile nutrient medium, 3000 units must be filled and no contaminated unit must be found after the incubation period. (However, see section 9.19)
9.10 For the initial validation of a new process or installations, a sufficient number of consecutive environmental distribution cycles should be performed to ensure that the results obtained are consistent, valid and provide an acceptable level of certainty as to sterility. Thus, at least three separate, consecutive and successful cycles should be performed for each operator, team or position to provide acceptable initial validation for a given process. (For revalidation, see section 11)
9.11 The volume dispensed per unit should be equivalent to the fill volume of a normal manufacturing cycle where possible. In the case of large volume containers, a smaller quantity may be used, provided that the entire internal surface of the container and any closure device used, for example, by stirring or inversion, are wetted with the medium, or by inverting the container once the incubation period has begun. It is a good practice to take similar measures to ensure complete wetting of the internal surface when full volumes are dispensed under normal conditions.
9.12 Immediately after dispatch, all completed units should be examined for leaks or damage. In this context, any method of detection of leaks based on the use of heat should obviously not be used. All fugitives or damaged containers should be rejected.
