Process Validation: Aseptic Processes for Pharmaceutical Products

Contents :

1. Introduction
2. Validation - general aspects and terminology
3. Debugging and protocol control
4. Staff
5. Data Review and Registration of Study
6. Laboratory
7. Environmental Considerations: Standards, Qualification and Monitoring for the Cleanroom
8. Qualification and maintenance of equipment
9. Environmental Distribution Studies (Solution Products)
10. Environmental Distribution Studies (non-solution products)
11. revalidation
12. Documentation

• GMP Committee Members

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 by less rigorous autoclaving cycles adapted to the process. 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 the 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 specifications	Qualification of the equipment		Qualification of the process
	Qualification of the installation	Operational Qualification
Sometimes called previdation
Global validation process

2.5 Validation is also considered to include three possible aspects or strategies: prospective validation, 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 carried out 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 understood
• the specifications and the design of the equipment are adequate
• the equipment is properly installed and maintained and is obviously operating according to its specifications and design
• the 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 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 being 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 room
• determination of the rate of flow of air on the surface of each air intake filter
• air exchange rate of the room
• particle count in the air of the room
• difference in air pressure and air flow pattern in the room
• lighting, heating, humidity
• checking the efficiency of air filters at workstations
• determination of airflow velocity at the surface of air filters at workstations
• particle 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 environment
• Microbiological monitoring
• Checking 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 pieces of equipment clearly not within the limits of this guide. Note, however, essential requirements, namely:

• confirmation that the equipment has been manufactured to the specifications
• confirmation that the equipment has been properly installed and equipped with all services, auxiliary equipment and necessary instruments in working order
• confirmation that the equipment can operate regularly, within pre-determined limits, on its defined operating range.

8.2 There must be confirmation that the equipment for the treatment is qualified before any subsequent study can not be considered valid.

8.3 For the results of the validation study remain valid for regular production, we should develop a complete regular maintenance program, detailing each activity as well as its frequency, time, time machine or any another time base. The chosen time base should be clearly defined for each operation.

8.4 Unless such a program is developed and implemented, and that the manufacturing equipment and auxiliary instruments remain not in the same state as validation studies, any insurance provided by these studies could be compromised.

9. media fill studies (products in solution)

9.1 In the technique of "middle distribution" or "stock distribution" preparing a liquid microbial growth medium that is distributed by simulating a normal manufacturing operation. The nutrient medium is processed and handled in a manner that simulates as closely as possible the manufacturing process "normal", including exposure to contamination (from operators, the surrounding environment, equipment and surfaces) . The sealed environment of containers thus obtained are then incubated in pre-established conditions and examined Microbial growth is research evidence there, these results provide an indication of the rate contaminated units. 

NOTES:

• Different types of containers require different methods of sterilization. For example, the sterilization of glass vials will probably be by dry heat and the plastic bottles, by irradiation or exposure to ethylene oxide.
• All other components eg pacifiers or dropper, will also be pre-sterilized by a validated method appropriate.
• The flowchart in the middle of distribution in ampoules will be similar to the above chart, without operations related to corks and capsules, etc.

9.2 It is important to realize that the media fill testing is often, among other things, an audit of the operator aseptic techniques. In this situation, operators can hardly ignore that the distribution is made with nutrient medium and are themselves, to some extent, "tested". Therefore, they may take more precautions than usual, preventing the accurate simulation of the usual method. We should do everything to ensure that operators behave as usual in the middle of distribution and vice versa (which may be important), they do not depart from the high standards adopted during the studies validation during regular operations.

9.3 Another problem noted is the risk of contamination of laboratories and equipment in the nutrient medium. If the process is well controlled and the media fill quickly followed by cleaning and disinfection, and (if necessary) of the sterilizing equipment, there should not be any contamination. Nevertheless, it is important to recognize this risk and act accordingly.

9.4 It should also be noted that, in itself, the distribution of a nutrient medium solution is not an acceptable validation of aseptic processes. The entire production cycle is to be simulated, since the distribution and reconstitution of the powdered medium by using the normal manufacturing conditions, until the distribution and sealing. The operators (and the number of operators), number and type of filtration, etc. should be the same as under normal conditions, as the retention time in the mixing vessels, temporary storage tanks, etc. The general activity should be at a normal level, and we should not try to take "special" care to ensure that the trial will be successful. In fact, s'there must be a change from normal, can only be in the direction of greater, not lesser, difficulties to overcome microbiologically.

9.5 Before a distribution environment for validation purposes is validly business, all measures of equipment qualification and calibration instruments must be completed and the appropriate certification (see p. Ex . sections 6 and 8). It should also confirm and certify clean rooms for all treatment stages are in line with environmental standards. (See Section 8)

9.6 Normal operations control and in-process monitoring (see section 8) should be performed during the media fill tests.

9.7 The used liquid nutrient medium should meet the following criteria.

• Selectivity: 
  The media should have a low selectivity, that is to say, allow the growth of the widest range of microorganisms that may be encountered.
• Clarity: 
  Once reconstituted, the environment should be clear to allow observation of any sign of growth after incubation.
• Filterability: 
  When the simulated method comprises a filtration step, the liquid medium should be filtered through a microbial retentive filter of the same type and of the same quality as that which will be used to filter the real product. The soybean casein lysate medium, sometimes called "tryptic soy broth" is perhaps the most commonly used liquid medium. However, other formulations (e.g., the extract tryptone glucose yeast, the perfusion medium brain heart, etc.) can also be used, provided they meet the above criteria.

9.8 should sterilize the liquid medium or by filtration (if this step is normally part of the simulated operation) by presterilization heat and cooling to room temperature before proceeding.

9.9 The number of units to be completed by cycle should be high enough to detect with high probability low levels of microbial contamination. For example, to be able to detect with a confidence level of 95% a contamination rate of one per thousand units filled (i..e. 0.1%) with a sterile nutrient medium, one must complete 3,000 units 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 new facilities, one should perform a sufficient number of consecutive cycles middle of distribution to ensure that the results are systematic, valid and they provide an acceptable level of certainty about infertility. Thus, at least three cycles separate consecutive successful and should be done for each operator, team or position so as to provide an acceptable initial validation for a given process. (For revalidation, see Section 11)

9.11 The volume dispensed per unit should be equivalent to the filling volume of a normal manufacturing cycle whenever possible. In the case of large volume containers, a smaller quantity can be used, provided that to ensure wetting with the medium throughout the inner surface of the container and any closing device used, for example, by stirring or inversion, or returning the container after commencement of incubation period. It's a good habit to take similar measures to ensure complete wetting of the inner surface when full volumes are distributed in normal conditions.

9.12 Immediately after the distribution, one should consider all units met in order to detect possible leaks or damage. In this context, any leak detection method based on the use of heat should obviously not be used. All fugitives or damaged containers should be rejected.

9.13 Incubation filled units should immediately follow the distribution and leaks, and continue for 14 days.

9.14 The incubation temperature should be between 30 and 35 ºC. The incubation temperature should be monitored and maintained throughout the incubation period.

9.15 Test Witnesses: The media used in the evaluation must undergo growth stimulation test; inoculation of 10 to 100 organisms per container is suitable to show the body's growth characteristics.

9.16 Reading the results: After 14 days of incubation, visually should consider all units filled and incubated to search for possible microbial growth. The infected units will be detected by the turbidity of the medium. All contaminated units should be examined in the laboratory, and organizations identified contaminants, if possible the species close, so we can take preventive measures. For the results of the media fill test to be valid, all inoculated control units expected to show growth.

9.17 The level of contamination of a media fill testing should be calculated as follows:

The number of failures observed	0	1	2	3	4	5	6	7	8	9	10
upper confidence limit of 95%	3	4.74	6.3	7.75	9.15	10.51	11.84	13.15	14.43	15.71	16.96

9.18 Acceptance criteria: A commonly accepted limit is 0.1% at a confidence level of 95%.

9.19 However, it is important to realize that media fill testing with 3000 units only partially simulate normal production cycle. Actual production cycles will likely be much higher. The contamination rate determined from a distribution medium will therefore depend sampling error; thus, the detection of three units contaminated on 3000 units filled may indicate possible contamination rates significantly higher than 0.1% in a real production cycle.

9.20 The table below shows the maximum number of allowed units in contaminated nutrient medium allocation cycles for a contamination rate of up to 0.1% with a 95% confidence interval.

The table below shows the maximum number of allowed units in contaminated nutrient medium allocation cycles for a contamination rate of up to 0.1% with a 95% confidence interval.

Units filled with medium	Contaminated units permitted
3000	0
4750	1
6300	2
7750	3
9150	4
10510	5
11840	6
13150	7
14430	8
15710	9
16960	10

For example, to obtain the certainty (95%) of the conformity rate limit of 0.1% in a production batch of more than 100 000 units, should be filled units 4750 medium which not more than one would contaminated, or 6300 units with not more than 2 contaminated, and so on.

9.21 For smaller batches than 3000 units, the minimum number of containers used for the test to simulate aseptic operations using a sterile nutrient medium should be equal to the size of the commercial lot and no contaminated unit should not be found after the incubation period.

Thus, for a method wherein the normal batch size is 20,000 units, a filler 4340 units provide certainty, to a confidence level of 95%, a level of contamination at most 0.1 % if we do not find more than one contaminated unit.

9.22 To demonstrate compliance to a contamination limit of one per 10,000 (0.01%), it would be necessary to use much more full of middle units. For example, for a production run of 50,000 units, it would fill more than 46 000 units and does not find more than one contaminated unit.

9.23 These statistical considerations reveal an obvious practical problem regarding the number of units to be filled medium and incubated, especially if we want to demonstrate a likelihood of a low infection rate (p. Ex. Less than 0.1 %) in normal size of production batches. Manufacturers should determine (according to their specific conditions and the size of their production runs) the number of units required for media fill tests, and allowed contamination level that would provide adequate assurance of sterility in real conditions. Based purely on the practical limitations of the test method itself, a contamination rate of 0.1%, if infrequent, may be considered acceptable for the media fill testing.Regular contamination rates or currents of 0.1% or more (in the middle of distribution tests) should be unsatisfactory.

9.24 Although it is not statistically rigorous to simply add the data obtained from separate events and then process that data as though they had been collected in a single event, a series of "good" results in media fill tests obtained over time (assuming a reasonably comparable conditions, etc.) can be reassuring, even if we can not accurately determine the insurance.

10. middle distribution studies (Other products in solution)

The same general principles, conditions and statistical considerations outlined in Section 9 apply; however, the various types of non-sterile products in solution require different adjustments to previously described procedures. In all the operations based on the use of growth media, it is vital to control contamination of equipment, surfaces, etc. the middle. All media fill studies should be quickly followed by meticulous operations of disinfection and sterilization cleaning.

10.1 Sterile Powders:

The use of media fill validation technique for the distribution of sterile powders presents special problems; in fact, it will probably use the equipment, techniques, or additional or different manipulations of those used in ordinary production. In such conditions, the middle of distribution can not be considered categorically as an exact simulation of the process. Yet it is an unavoidable reality. A number of approaches, listed below, have been proposed and used.

10.1.1 The normal process is simulated as accurately as possible, but instead of distributing a powder, is distributed a sterile liquid medium. This approach is essentially the same as that described for the product in solution (section 9 above) and does not simulate the distribution of powder which occurs in the real process.

10.1.2 The normal process is simulated as accurately as possible using a sterile inert dry powder instead of the substance or natural product. Lactose, mannitol and polyethylene glycol 8000 are examples of powders "simulation" that have been used. There are two possible variations of this approach:

1. distribute the inert powder selected from the containers (eg. ex. ampoules or vials) already filled with liquid medium steriled
2. distribute the first inert powder and then add the sterile liquid medium. In both variations, a powder distribution is simulated, but there is an unusual additional step (i.e. d. The distribution of the liquid growth medium).

10.1.3 Pour the medium in a sterile dry powder in containers, simulating the normal powder distribution operation, and add, under aseptic conditions, a sterile aqueous diluent so as to prepare a liquid medium. As in section 10.1.2, a powder distribution is simulated, but adding an operation.

10.2 Whatever the approach, it is important to ensure that any combination powder-middle-thinner used does not inhibit growth by hyperosmolarity and has no antimicrobial effect.

10.3 suspension products : Simulate all natural process as closely as possible, using a sterile inert powder instead of the normal powder. Micronizing (if it is part of the normal process) and suspending, by using the medium of sterile liquid growth instead of the normal liquid phase of the product in suspension. Fill as usual and incubate. (The same comments section 10.2 apply)

10.4 Lyophilized Products : Simulate all natural processes (. Ie of the main solution preparation, distribution of the solution, loading the freeze dryer, execution of the lyophilization cycle, sealing or closure of containers, inspection) but using liquid growth medium (powder dissolved and sterilized) instead of the usual product. The actual freeze-drying the solution medium is not feasible, but the exposure and the holding time in the freeze dryer should be performed as in the normal cycle.

10.5 semi-solid products (eg ointments and sterile creams..) Simulate all natural processes as closely as possible, using a sterile liquid growth medium which has been given a consistency similar to that of the normal product by uploading e.g. agar (about 4 g per liter) or carboxymethylcellulose.

11. Revalidation

11.1 After the first aseptic process validation, the media fill tests and process simulations should be repeated to an extent and at a rate that will depend on the occurrence of events or changes which affect the risk of contamination microbial for the process and product. Material changes to equipment or facilities, personnel changes, adverse trends in the results of monitoring of the surrounding environment, and failure to sterility tests can all indicate the need to immediately implement a comprehensive protocol validation process (ie d. a minimum of three consecutive cycles of successful media fill), officials installations being decommissioned upthat the problems have been resolved and that the results of the three distribution tests have been evaluated and found acceptable.

11.2 In the absence of significant changes, or any other cause for concern, the minimum frequency of tests should be two times a year by operator position or team for each production line. For single station operations, the minimum frequency should be three times a year by production line.

12. Documentation

The following documents should be prepared in summary form for inspection and evaluation by the competent authorities.

12.1 Overview

In the overview of the process validation protocol should be indicated the steps followed in the proper order, and other relevant data, including:

1. the approach;
2. data to justify the approach, based on the characteristics of the product to be treated;
3. a brief description of the changes to the equipment;
4. changes to the protocol in the light of the test results.

12.2 Prevalidation

12.2.1 Complete description of the equipment and auxiliary systems for aseptic filling and reports confirming the successful installation in accordance with the methods of installation qualification certifying that the equipment and systems, in their current state, work regularly within defined limits.

12.2.2 Indication of environmental standards designated for each stage of manufacture and certification of conformity to any controlled environment standards identified during the studies (see section 7).

12.3 Qualification method

12.3.1 Summary of methods and controls used for the following operations, both in the normal chain of production and during the validation tests:

• distribution of ingredients
• water quality and water supply
• cleaning, disinfection or sterilization (as appropriate) of equipment, surfaces and services
• sterilization of equipment, containers and piping
• verifying the integrity of the filters
• installation, startup and adjustment of the equipment
• dressing Staff

12.3.2 Full Report on the qualification of the method, comprising the following elements:

• medium used
• volume distributed
• number of units filled
• number of rejected fugitives
• incubated number of units
• incubation temperature
• incubation time
• control organisms used
• results of the filter integrity verification tests
• recording of all monitoring results and in-process control
• summary of the number of employees involved in the studies and their qualifications
• policies and reports on interventions permitted operators (see 4.11)
• written protocols for all laboratory testing and official reports of the results of all tests, and evaluation of these results by the criteria established in the protocols of the study.

12.3.3 If there is a retrospective validation, details of assessment requirements analysis and batch processing, including the results of in-process controls should be compiled for the period. Evidence of the equivalence of production conditions of these lots to the current process conditions, including calibration and maintenance records are required. It should also provide the parts ensures that failures and deviations detected in the case of process or product of the Treaty have been taken into account in the assessment.

12.4 Expertise

It is important to make an assessment of the entire study against the protocol requirements as outlined above and to draw conclusions at each stage stated. The final conclusions must indicate whether requirements have indeed been met.

The evaluation should include an assessment of the ability of calibration and maintenance programs of the equipment and instruments to maintain the conditions that have been validated (see Sections 6, 7 and 8). The assessment should also specify the processing conditions and the means of control necessary to ensure that the validated conditions are maintained.

The assessment should be signed by duly authorized representatives of the organization, having participated in developing the protocol and with appropriate expertise. The study must be finally approved by the head of the team responsible for the validation and the head of the quality control department.

GMP Committee Members

Name / Title / Office / Location

France Dansereau, President 
Manager, Unit Inspections, HPFBI Footnote Page1 
Ottawa, ON

Kim Dayman-Rutkus 
Interim Manager, Policy and Regulation Division, HPFBI 
Ottawa, ON

Richard Ferland 
Officer of Mutual Recognition Agreements (MRAs), IDGPSAI 
Longueuil, QC

Francisco Fernandes 
Compliance Specialist, HPFBI 
Scarborough, ON

Taraz Gedz 
Bureau of Pharmaceutical Sciences 
Ottawa, ON

Denis Girard 
Directorate vets drugs 
Ottawa, ON

Raymond Giroux 
Drug Specialist, HPFBI 
Longueuil, QC

Alicja Kasina 
Drug Specialist, HPFBI 
Halifax, NS

Daryl Krepps 
Senior Regulatory Advisor, BPBTG Footnote Page2 Footnote page
Ottawa, ON

Stephen McCaul 
Officer of Mutual Recognition Agreements (MRAs), HPFBI 
Scarborough, ON

Medic Ndayishimiye, Secretary 
Compliance Officer HPFBI 
Ottawa, ON

Randy Stephanchew 
Specialist GMP HPFBI 
Winnipeg, MB

Stéphane Taillefer 
Compliance Specialist, IDGPSAI 
Longueuil, QC

Sheila Welock 
Spécilaiste drugs, HPFBI 
Burnaby, BC