Re-validation of processes. Validation, verification, special process. Analytical Method Validation Parameters

- legalization, approval, legalization, ratification
(general civil law);

- a process that allows you to determine how accurately, from the perspective of a potential user, a certain model represents given entities the real world
(system Programming);

- a procedure that gives a high degree of confidence that a particular process, method or system will consistently lead to results that meet predetermined acceptance criteria; in particular, validation technological processes carried out using samples of at least three batches of a real product in order to prove and provide documentary evidence that the process (within the established parameters) has repeatability and leads to the expected results in the production of an intermediate product or a finished product of the required quality; validation of analytical methods consists in determining: accuracy, reproducibility, sensitivity, stability (interlaboratory reproducibility), linearity and other metrological characteristics
(GMP - Good Manufacturing Practice, is a mandatory requirement in the manufacture of medicines).

With regard to quality management systems according to the ISO 9000 series:

Validation- confirmation, based on the provision of objective evidence, that the requirements for a particular use or application have been met
(ISO 9000: 2005)

Validation- confirmation by examination and presentation of objective evidence that the specific requirements for a particular application have been met.
Notes:

1. In design and development, approval means the examination of a product to determine if it meets a customer's needs.
2. Approval is usually done on the final product in certain conditions exploitation. It may be needed in the earlier stages.
3. The term "approved" is used to indicate the corresponding status.
4. Multiple approvals can be made if different uses are intended.

(ISO 8402: 1994, clause 2.18)

As defined by PIC / S, these are:
"Actions that, in accordance with GMP principles, prove that a particular method, process, equipment, raw material, activity or system actually leads to the expected results."

Validation

Validation studies should promote good manufacturing practice; they should be carried out in accordance with established procedures. Results and conclusions should be documented in protocols.

If a new production recipe is introduced or new way manufacturing, actions shall be taken to demonstrate their suitability for batch production. It must be demonstrated that the established process, using the specified substances and equipment, can consistently produce the product of the required quality.

Significant changes to the manufacturing process, including any change to equipment or materials that may affect product quality and / or process reproducibility, must be validated.

Processes and procedures should be periodically revalidated to ensure that they are still capable of delivering the expected results.

Validation and its documentation

The goal of validation is simple: to prove that the validated object actually produces the expected results. In other words, the validation must show that the manufacturer has complete control over the production process. Validation is an integral part of “quality assurance”, showing that the manufacturer understands the reasons for the variability of the process and, in general, understands which parameters need to be controlled to ensure the stability of the process. Effective validation is based on risk management and state of the art science.

The validation process procedures should be recorded in a series of protocols and the results of the validation should be recorded or reported.

These documents are used in various forms when obtaining marketing authorization and inspection in accordance with GMP rules and also for internal production purposes, so that the organization's management can be sure that it is in control of its processes. The documentation of the validation process is the basis for the necessary regulation. But in order to avoid
of the error that is often encountered in the implementation of GMP principles in Russia, we deliberately discuss the process of documenting validation in the section on documentation.

There is a rather serious difference between the Russian and international approaches. In the Russian GMP rules, validation "consists in the documented confirmation of the conformity of equipment, production conditions, quality of raw materials and finished products to the current regulations and / or the requirements of regulatory documents." This approach is outdated. Its consequences are quite harmful. From different publications one might get the impression that the validation process is nothing more than a documentation process, or that words such as “validation” “verification”, “qualification” and “testing” are, in fact, analogous to each other. The lack of understanding of "validation" reinforces the misunderstanding of GMP, and creates a situation where staff resist the introduction of GMP, simply accepting it as "an ever-growing mountain of documents."

In GMP EC (and by the way, GMP FDA), validation is a regular study of systems, processes, engineering complexes and, of course, the pharmaceutical product itself, in order to provide a high level of confidence that the processes have been properly designed and controlled.

Effective validation requires a risk-based approach, full understanding of manufacturing processes and increasing their resilience through the introduction of new technologies. Thus, validation is a dynamic process. This fact obviously presents some difficulties for regulators.

From the point of view of drug developers and manufacturers, validation can provide the following benefits:

• deeper understanding of processes and therefore, reducing risk while preventing problems and ensuring smooth process control;
• reducing the cost of eliminating deficiencies;
• reducing the risk of non-compliance with regulatory requirements.

After complete validation of the process, it is possible that the number of controlled parameters at the end of the process will decrease. Developers, fully understanding those parameters that affect the variability and, therefore, the stability of the process, have the necessary information to control the process, for example, by reducing the variability or increasing its speed. Although “validation” is an integral part of “quality assurance”, it shows the relationship between validation and the management system. In order to effectively conduct validation, the company's management must determine its policy in this matter. One of the first elements that an FDA or PIC / S inspector wants to check is the validation policy.

1. (12.10) The manufacturer should document the general validation policy, its objectives and principles, including the validation of processes, cleaning procedures, analytical procedures, control procedures during manufacturing, computerized systems and in relation to those responsible for the development, verification, approval and documenting each stage of validation.
2. (12.11) Critical parameters and (or) characteristics, as a rule, should be determined at the development stage or on the basis of data from preliminary work experience; it should also determine the ranges of values ​​of these critical parameters and / or characteristics necessary to ensure reproducibility of the process. In this case, it is necessary:

• to determine the critical characteristics of the FS as a product;
• indicate the process parameters that can affect the critical indicators of the quality of the FS;
• establish the range of values ​​of each critical process parameter that is supposed to be used when serial production and process control.

1. (12.12) Operations that are considered critical to the quality and purity of the drug substance are subject to validation.

Validation documentation (12.2)

1. 12.20 A validation protocol should be developed for each process to be validated. This protocol should be checked and approved by the quality department (s) and other relevant departments.
2. 12.21 The validation protocol should identify the critical process steps and acceptance criteria, as well as the type of validation to be performed (e.g. retrospective, prospective, concomitant) and the number of production runs.
3. 12.22 The validation report should cross-reference the validation protocol and summarize the results obtained, explain any deviations found with appropriate conclusions, including recommended changes to correct deficiencies.
4. 12.23 Any deviations from the validation protocol should be documented with appropriate justification.

1. (12.30) Qualification of critical equipment and ancillary systems should be completed prior to process validation work. Qualification is usually carried out in the following steps (individually or collectively):

• project qualification: documented confirmation that the proposed design of production facilities, equipment or systems is suitable for the intended use.
• installation qualification: documented confirmation that the installation of premises, systems and equipment (installed or modified) was carried out in accordance with the approved project, the manufacturer's recommendations and (or) the requirements of the drug manufacturer.
• Operational qualification: documented confirmation that premises, systems and equipment (installed or modified) function in accordance with their intended purpose in all envisaged modes of operation.
• Operational Qualification: Documented evidence that rooms, systems and equipment, when used together, operate efficiently and reproducibly in accordance with established process requirements and characteristics.

Process validation approaches (12.4)

• a) (1) Critical quality indicators and critical process parameters are determined;
• b) (2) appropriate acceptance and control criteria are established during manufacturing;
• c) (3) there were no significant process failures or product defects due to reasons not related to operator errors or equipment failures;
• d) (4), the profiles of impurities for this PS were established.

1. (12.45) The batches selected for retrospective validation should represent a representative sample of all batches produced during the validated period, including any batches that do not meet specifications. Moreover, the number of such batches should be sufficient to prove the consistency of the process. Archival samples may be tested to provide data for retrospective process validation.

Process validation program (12.5)

1. (12.50) The number of production runs required for validation should depend on the complexity of the process or the significance of the process changes to be considered. For prospective and concurrent validation, data from three consecutive production batches of good quality products shall be used. However, there may be situations when additional production cycles are needed to prove the consistency of the process (for example, complex pharmaceutical production processes or long-term pharmaceutical production processes). To assess process consistency in retrospective validation, it is usually necessary to examine data for 10 to 30 consecutive series, but this number can be reduced with appropriate justification.
2. 12.51 During process validation studies, critical parameters should be monitored and verified. Process parameters that are not related to quality, such as variables controlled to reduce energy consumption or equipment use, may not be included in the process validation.
3. 12.52 Process validation should confirm that the impurity profile for each DS is within specified limits. The impurity profile should be similar (or better) to the previously obtained profile and (where applicable) to the impurity profile established during the development of the process or batch used for basic clinical and toxicological studies.

Periodic inspection of validated systems (12.6)

1. (12.60) Systems and processes need to be periodically assessed to confirm that they continue to function correctly. Unless significant changes have been made to the process or system and the quality review has confirmed that the system or process is consistently producing material that meets specifications, there is generally no need for revalidation.

1. (12.70) Cleaning procedures should generally be validated. Purification validation is carried out in cases in which contamination or transfer of substances pose the greatest danger to the quality of the PS. For example, in the early stages of a process, it may not be necessary to validate equipment cleaning procedures if residues are removed in subsequent cleaning steps.
2. 12.71 Validation of cleaning procedures should reflect the actual use of the equipment. If different APIs or different intermediates are manufactured on the same equipment and the equipment is cleaned in the same way, then a representative intermediate or API can be selected for cleaning validation. This choice should be based on data on solubility and purification difficulties, as well as on the calculation of the limit for the content of residues, taking into account their activity, toxicity and stability.
3. 12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, monitored and controlled parameters and analytical procedures. The protocol should also indicate the types of samples to be taken, methods of sampling and labeling.
4. 12.73 For the detection of both insoluble and soluble residues, sampling methods should include, as appropriate, swabs, swabs or other methods (eg direct extraction). Sampling methods used should be capable of quantifying residue levels on equipment surfaces after cleaning. Sampling by swabbing may not be feasible if product contact surfaces are difficult to access due to the design of the equipment (for example, internal surfaces of hoses, transport pipelines, containers of reactors with narrow hatches, as well as small complex equipment such as micronizers and microsprays) and / or if there are process restrictions (for example, handling toxic substances).
5. 12.74 Validated analytical procedures should be used that are sensitive enough to detect residues or contaminants. The detection limit of each analytical procedure must be sufficient to detect a specific acceptable level residue or contaminant. For the method, it is necessary to establish the attainable level of extraction of the substance. Residue limits should be realistic, achievable, verifiable and based on the most harmful residue. The limits can be set based on the minimum amount of PS or its most harmful component with known pharmacological, toxicological or physiological activity.
6. (12.75) For processes in which there is a need to reduce the total microorganisms or endotoxins in PS, or for other processes where such contamination may be of importance (for example, the production of non-sterile PS used for the production of sterile medicinal products), research on cleaning and / or sanitizing equipment should be carried out in relation to contamination with microorganisms and endotoxins.
7. 12.76 The manufacturer should monitor cleaning procedures at regular intervals after validation to ensure that these procedures are effective when used during the ongoing process. The cleanliness of the equipment, where practicable, should be controlled by analytical testing and visual inspection. Visual inspection allows you to detect significant accumulations of contaminants on small areas that may not be detected in any other way during sampling and (or) analysis.

Validation of analytical procedures (12.8)

1. (12.80) The analytical methods used should be validated. The suitability of all test methods used must, however, be verified under actual conditions of use and the results documented.
2. 12.81 Validation of methods should be carried out taking into account the characteristics given in the analytical method validation manuals. The scope of the analytical validation performed should depend on the purpose of the analysis and the stage of the pharmaceutical manufacturing process.
3. 12.82 Prior to validation of analytical procedures, an appropriate qualification of the analytical equipment should be carried out.

539. (12.83) A complete record of any changes to a validated analytical procedure should be maintained. Such records should reflect the reason for the change and the associated data to confirm that the change leads to results that are as accurate and reliable as the results obtained using the accepted methodology.

Legalization, approval, legalization, ratification
(civil law);

A process that allows you to determine how accurately, from the perspective of a potential user, a certain model represents given entities of the real world
(system Programming);

A procedure that gives a high degree of confidence that a particular process, method or system will consistently produce results that meet predetermined acceptance criteria; in particular, the validation of technological processes is carried out using samples of at least three batches of a real product in order to prove and provide documentary evidence that the process (within the established parameters) has repeatability and leads to the expected results in the production of an intermediate product or a finished product of the required quality; validation of analytical methods consists in determining: accuracy, reproducibility, sensitivity, stability (interlaboratory reproducibility), linearity and other metrological characteristics
(GMP - Good Manufacturing Practice, is a mandatory requirement in the manufacture of medicines ).

With regard to quality management systems according to the ISO 9000 series:

Validation- confirmation, based on the provision of objective evidence, that the requirements for a particular use or application have been met ( ISO 9000: 2005)

Validation- confirmation by examination and presentation of objective evidence that the specific requirements intended for the specific application have been met.
Notes:
1. In design and development, approval means the examination of the product to determine whether it meets the needs of the customer.
2. The approval is usually carried out on the final product under certain operating conditions. It may be needed in the earlier stages.
3. The term "approved" is used to indicate the corresponding status.
4. Multiple approvals can be made if different uses are expected.
(ISO 8402: 1994 Clause 2.18)

Let's analyze the requirements of the ISO 9001 standard:
ISO 9001 Clause 7.3.6: Design and development validation should be carried out in accordance with planned arrangements to ensure that the resulting product meets the requirements for the specified or intended use.
ISO 9001 Clause 7.5.2: Validation of production and service processes. The organization shall confirm all production and service processes whose results cannot be verified through consistent monitoring or measurement. These include all processes, the deficiencies of which become apparent only after the start of use of the product or after the provision of the service. Validation should demonstrate the ability of these processes to achieve planned results.
ISO 9000 note 3 3.4.1: The process in which it is difficult or economically impractical to confirm the conformity of the final product is often referred to as " special process ".

Generally accepted requirements for special manufacturing processes ensuring their validation:
1) certification of the production process (technology, methodology, work instructions ...)
2) qualification of production equipment (calibration of welding machines or robots, spray guns and paint supply systems ...)
3) certification of materials (electrodes, gas, fluxes, paint, solvents, primers ...)
4) certification of personnel (qualification requirements for welders or operators of welding robots, adjusters, service companies ...)
with appropriate documentary evidence. ( A. Oreshin)

Specialist. process (SP) should be in a controlled environment.
Controlled conditions include:
- availability of information describing the characteristics of products and joint venture;
- availability of regulatory, design and technological documentation;
- use of suitable equipment;
- availability and use of control and measurement instruments;
- carrying out control, measurements and tests;
- implementation of activities for the implementation of the joint venture;
- availability of qualified and certified personnel of the joint venture;
- re-validation;
- availability of records containing the results achieved or evidence of the activities carried out during the implementation of the joint venture. ( V. Zolotukhin)

Validation, verification, special process

What is the difference between validation and verification?
ISO 9000 defines these terms as follows:
"Verification- confirmation, based on the provision of objective evidence, that specified requirements have been met. "
"Validation- confirmation, based on the provision of objective evidence, that the requirements for a particular use or application have been fulfilled. "
It would seem that the definitions almost coincide, and if not completely, then in a significant part. And, nevertheless, verification and validation are fundamentally different actions.
Let's figure it out.
Already the translation of these terms from English provides some food for understanding the difference: verification - verification, validation - legalization.
To make it easier to understand, I will immediately give an example of a typical verification: testing a program or testing equipment. With certain requirements in hand, we test the product and record whether the requirements are met. The result of verification is the answer to the question "Does the product meet the requirements?"
However, it is not always possible to apply a product that meets the established requirements in a specific situation. For example, a medicine passed all the required tests and went on sale. Does this mean that it can be used by some specific patient? No, because each patient has its own characteristics and for this particular medicine can be destructive, i.e. someone (the doctor) must confirm: yes, this patient can take this medicine. That is, the physician must perform validation: to give legal force to a specific application.
Or another example. The enterprise produces pipes intended for burying in the ground, in accordance with some technical specifications ( Specifications). The products comply with these TUs, but an order has been received for pipe laying on the seabed. Can pipes corresponding to the existing specifications be used in this case? It is validation that gives the answer to this question.
It is easy to see that another difference is that verification is always performed, but there may be no need for validation. It only appears when requirements arise related to a specific application of the product. If a pharmaceutical plant produces drugs, then it will only check their compliance with the requirements, and will not deal with the problems of using specific drugs by specific patients. Or the same AvtoVAZ.
Thus, we can state the following:
verification - carried out almost always, performed by the method of checking (comparing) the characteristics of the product with the specified requirements, the result is a conclusion about the conformity (or nonconformity) of the product,
validation - carried out if necessary, performed by analyzing the specified conditions of use and assessing the compliance of product characteristics with these requirements, the result is a conclusion about the possibility of using the product for specific conditions.
ISO 9001 refers to these terms in two places. Let us check if the interpretation I have given is consistent with the content of Sections 7.3.5, 7.3.6 and 7.5.2.
"7.3.5. Design and development verification. Verification should be carried out in accordance with the planned arrangements (clause 7.3.1) to ensure that the design and development output meets the input requirements:".
"7.3.6. Design and development validation. Design and development validation should be carried out in accordance with planned arrangements (clause 7.3.1) to ensure that the resulting product meets the requirements for the specified or intended use, if known. Where as practicable, validation should be completed prior to delivery or use of the product. "
It is easy to see that my interpretation is in complete agreement with the text of these sections. At the same time, I would like to draw your attention to the fact that in clause 7.3.5 it is said about the conformity of the output data, and in clause 7.3.6 - to products. This is essential! This means that the validation is not carried out for the output data, but for the products designed for specific conditions. For example, in the activities of the institute for the development of standard projects of residential buildings, validation is not required - only verification. But for the activity on the development of a project for the construction of a residential building according to the same standard design, but in a specific place, validation is already necessary.
7.5.2 Validation of production and service processes. The organization shall validate all production and service processes whose results cannot be verified through consistent monitoring or measurement. These include all processes whose deficiencies become apparent only after the product is used or after the service has been provided. Validation must demonstrate the ability of these processes to achieve planned results. "
There are no discrepancies here either. However, it should be noted that in cases falling under clause 7.5.2, product characteristics cannot be measured directly and will be evaluated indirectly (for more details, see the lecture on special processes).
Question: what is the activity of the Quality Control Department?
Answer: this is verification.
Question: what should be attributed to the activities of auditors?
Answer: to verification.
Question: What is the function of the signing act on the commissioning of an object (service, etc.)?
Answer: it does validation.

Defining a custom process

Criteria for classifying a process as "special"
Of course, those who say that the standard does not directly define the term "ad hoc process" are right. This phrase appears in ISO 9000 3.4.1, Note 3 " A process in which it is difficult or economically impractical to confirm the conformity of the final product is often referred to as a "special process".
That is, the main feature of "specialty" here is the difficulty (problematicness) of conformity confirmation. Of course, such a criterion can hardly be considered unambiguous, since the degree of difficulty is unclear, above which the process can already be considered "special".
On the other hand, clause 7.5.2 of ISO 9001 establishes the requirement: " The organization shall confirm all production and service processes whose results cannot be verified through consistent monitoring or measurement.".
Let's try to answer several questions, the first of which is: why is clause 7.5.2 included in the ISO 9001 standard at all? Or in other words: what is the practical value of process validation for quality management?
The purpose of the quality management system (according to ISO 9001) is to ensure the stable quality of products, understood as compliance with customer requirements. From this point of view, we can call any production process effective (quality) if its result meets the specified requirements.
But the question is: what if the result cannot be directly compared with the requirements (measured)? How to determine the effectiveness of such a process? This is where Clause 7.5.2 comes into play, which says that such processes should be "validated" to "demonstrate the ability of these processes to achieve planned results." Those. cannot verify the result, then confirm the "correctness" of the process, proceeding from the assumption that the "correct" process gives the "correct" result.
There is an obvious commonality between the provisions of Note 3 of clause 3.4.1 of ISO 9000 and clause 7.5.2 of ISO 9001: both are related to confirmation of product conformity. But there is also an equally obvious difference: if ISO 9000 speaks of "difficulty" (without defining its measure in any way), then ISO 9001 is more categorical: "cannot be verified", i.e. it is about "impossibility".
So can the processes for which the requirements are established in 7.5.2 be considered the very "special" processes? I suppose yes, because "impossibility" is the extreme degree of "difficulty."
The practical significance of deciding whether to classify a process as "normal" or "special"
The assignment (or not assignment) of a process to "special" is of practical importance and is carried out as part of the planning of the process provided for in section 7.1 of ISO 9001.
The fact is that, as I will try to show below, the "ordinary" and "special" processes are built in different ways, and this difference in structure is explained by different methods for determining the effectiveness of the process. Without going into subtleties, we can say that the effectiveness of the "normal" process is assessed by the compliance of the result with the specified requirements, and the effectiveness of the "special" process - by the compliance of the actions performed within the framework of the process, the established technology. In other words, we will call a "normal" process effective when its output meets the specified requirements, and "special" - when the technology for obtaining the output corresponds to the established one. Therefore, building a "normal" process, we must provide in it the operations of monitoring compliance with the requirements of the results at the intermediate and final stages of production, based on the measurements of these results. And when building a "special" process, the priorities will be different: we will include operations for monitoring compliance with production technology, based on records of compliance with the technology.
Can the process of providing a service be considered ad hoc?
Clause 7.5.2 contains the instruction: " To them["special"] processes refer to all processes whose deficiencies become apparent only after the product has been used or after the service has been provided".
As practice shows, this provision does not have an unambiguous interpretation among quality management specialists and requires a separate analysis, especially in terms of services.
First, I would like to draw your attention to the fact that the regulation speaks about the shortcomings of the process, not the product.
Secondly, I would like to show the fundamental difference between the production process with the following two block diagrams. material products from the service production process.

Now is the time to define what is service... By service I mean the activity of the manufacturer, the satisfaction of consumer requirements in which is achieved by performing actions, and not by transferring material products to the consumer. This definition is quite consistent with the widespread notion that in the provision of a service, its production and consumption coincide in time.
Reflecting on the nature of the service delivery process leads us to understand that
- the result of the service delivery process is the consumed service, i.e. service, the production and consumption process of which has ended,
- the consumer is a participant in the process of providing a service (is "inside" the process),
- an attempt to move the consumption of a service beyond the boundaries of the process of providing services leads to the "disappearance" of the output and, accordingly, the process itself.
The last position indicates that at point A (second figure) there are still no services as a result of the entire set of actions - after all, consumption occurs in the production process.
The next question that needs to be answered is whether the concept of “monitoring or measuring [the result]” is applicable to the service delivery process.
Obviously yes. The same telecommunication services give us such an example: a channel is organized for the client, through which the client's signal goes and all the agreed parameters are monitored. And after the completion of the service, we will be able to say on the basis of monitoring and measurement data whether the process was effective or not. Here is the key point: in order to establish the effectiveness of the process, we will not analyze the records on the performance (or not performance) of certain actions, on the compliance of these actions with the planned ones, but we will analyze the records on the parameters of the service, i.e. result data. In other words, if the client is dissatisfied, then in our defense we will not demonstrate to him that all the operations provided for by the technology were performed in strict accordance with the instructions, but we will show the results of monitoring and measuring the parameters of the service. And this in the most obvious way tells us that the process of providing a service in question cannot in any way be attributed to special ones.

Examples of demonstrating the practical application of the discussed criteria
In order to support the reasoning with examples, let's start with services.
Situation one... There is a forwarding company providing delivery services. She decides to include furniture in the shipment. The process needs to be planned, which makes it necessary to understand whether the process will be "normal" or "special". The main parameters of the service: delivery accuracy (time and place), cargo safety. Can these parameters be estimated (measured)? Of course, there are no obstacles to that. Can we confirm the effectiveness of the process based on the data of the assessment (measurement)? Without any doubts. Conclusion is a "normal" process.
Situation two... The same forwarding company decided to take care of delivering mail to Robinson. At the same time, the ship cannot come close to the island, the mail is fired by a catapult and the place of its landing is not always visible. The service parameters are the same. It is easy to see that in this case, not all parameters can be measured or assessed: for example, the place of delivery (either a parcel fell into a swamp, or hung on a tree) or safety. And in the absence of data on the result, on the effectiveness of the process, we will judge by the implementation of the technology: the bowstring was pulled with the necessary effort, the elevation angle was set, the azimuth was set exactly, the correction for the wind was made, etc. - i.e. did everything to get the desired result. The conclusion is a "special" process.
Situation three... We manufacture products - say, household bicycles - and we have the ability at every stage of production to measure the parameters of parts or assemblies and track their compliance with requirements. Before handing over the bike to the consumer, we will conduct a final check and say: here is the product, it fully complies with the established requirements. It is easy to see that we will classify such a process as an ordinary one.
Situation four... By order of NASA, we are making a bicycle for riding on Mars. In this case, one of the requirements says: the joints must have a special lubricant, after which the assembly must be performed and the product must be placed in a sealed container with a special gas environment. Obviously, such a requirement makes it impossible for us to carry out a final inspection of the bike, and when planning the process, we must recognize it as "special". In this case, fulfilling the provisions of paragraphs. 7.1 c) and d) we will provide for the collection of records of technology compliance and confirmation at the end production cycle based on these records that everything was done "right". This confirmation, in turn, will serve as evidence (albeit indirect) that the result of the process meets the requirements.
You can often find statements like "welding is a special process" or "painting is a special process". In my opinion, such statements are not entirely correct.
Let's assume that the result of welding is a weld. We have a regular order: pipes for an onshore gas pipeline and all the requirements are normal. What prevents you from checking all the parameters of the seam with the current diagnostic technique? Probably nothing. Those. we can well establish (confirm) the compliance of the result with the requirements of "sequential monitoring or measurement". But then another order came: we need to make a seam that must immediately break under a certain load. Well, how do we confirm compliance with this requirement? The process immediately changed from "ordinary" to "special".
Hence the conclusion: the process can be either "ordinary" or "special" - depending on the requirements for the result. In the same way, the "always special" process can become "routine" with the advent of new technologies and diagnostic devices.
And this is confirmed by the fact that the section. 7.1, speaking of process planning, emphasizes: "... for specific products "(see items b and c).
So the summary:
- "normal" and "special" processes differ in the methods of confirming the conformity of the result, and therefore, in order to correctly build a process for the production of a specific product, it is necessary to carry out an appropriate classification when planning the process,
- which should be based on the attribute "impossibility to confirm the conformity of the product by methods of measuring and monitoring its parameters" (i.e., the impossibility of confirming the effectiveness of the process by methods of measuring and monitoring the result),
- the use of which clearly shows the inconsistency of the widespread belief: all processes of service provision are "special". (A. Gorbunov)

Pharmaceuticals in the EU, in accordance with GMP principles, has adopted a definition according to which
validation is the formulation of evidence that the implementation or use of all processes, procedures, equipment, raw materials, products, activities or systems actually achieves the expected results.
The validation process consists of a sequence of different qualifications.
Qualification is an operation designed to prove that the equipment is working correctly and that it actually gives the expected results. Sometimes the concept of validation is extended to include the concept of qualifications.
Validation consists of the following processes:
- qualification of design documentation (Design Qualification - DQ) - verification of the description and development of the system;
- installation qualification (IQ) - verification of the system infrastructure's ability to support the system operation;
- Operational Qualification (OQ) - verification of the ability to function according to requirements;
- performance qualification (PQ) - verification of the company's ability to use the system.

1. ISO validation

2. What is different validation from verification?

3. Validation documents

4. XML and XHTML validation

5. GMP validation

6. What is EITI Validation?

Validation- this is legalization, approval, legalization, ratification (civil law);

Validation- this is that allows you to determine how accurately, from the perspective of a potential user, a certain model represents the given entities of the real world (system programming);

Validation- this is a procedure that gives a high degree of confidence that a particular process the method or system will consistently produce results that meet predetermined acceptance criteria; in particular, the validation of technological processes is carried out using samples of at least three series of real goods in order to prove and provide documentary evidence that process(within the specified parameters) has repeatability and leads to the expected results in the production of an intermediate product or finished goods required quality; validation of analytical methods consists in determining: accuracy, reproducibility, sensitivity, stability (interlaboratory reproducibility), linearity and other metrological characteristics

Validation ISO

With regard to quality management systems according to the ISO 9000 series:

Validation - Confirmation, based on the provision of objective evidence, that the requirements for a specific use or application have been met (ISO 9000: 2005)

Validation is the confirmation by examination and presentation of objective evidence that the specific requirements intended for a particular application have been met.

Notes:

1. In design and development, approval means the examination of the product to determine whether it meets the needs of the purchaser.

2. The approval is usually carried out on the final product under certain operating conditions. It may be needed in the earlier stages.

3. The term "approved" is used to indicate the corresponding status.

4. Multiple approvals can be made if different uses are expected. (ISO 8402: 1994, clause 2.18)

Analysis of the requirements of the ISO 9001 standard:

ISO 9001 clause 7.3.6: Design and development validation shall be carried out in accordance with planned arrangements to ensure that the resulting product meets the requirements for the specified or intended use.

ISO 9001, clause 7.5.2: Validation of production and service processes. shall confirm all production and service processes, the results of which cannot be verified by means of consistent monitoring or measurement. These include all processes, the deficiencies of which become apparent only after the start of use of the product or after the provision of the service. Validation should demonstrate the ability of these processes to achieve planned results.

ISO 9000 note 3 3.4.1: where it is difficult or economically impractical to confirm the conformity of the final product, is often referred to as a "special process".

Generally accepted requirements for special manufacturing processes to ensure their validation:

1) certification of the production process (technology, methodology, work instructions ...)

2) qualification of production equipment (calibration of welding machines or robots, spray guns and paint supply systems ...)

3) certification of materials (electrodes, gas, fluxes, paint, solvents, primers ...)

4) certification of personnel (qualification requirements for welders or operators of welding robots, adjusters, service companies ...)

with appropriate documentary evidence.

Specialist. (JV) must be in a controlled environment.

Controlled conditions include:

Availability of information describing the characteristics of products and joint venture;

Availability of regulatory, design and technological documentation;

Use of suitable equipment;

Availability and use of control and measurement instruments;

Control, measurements and tests;

Implementation of activities for the implementation of the joint venture;

Availability of qualified and certified personnel of the joint venture;

Re-validation;

Availability of records containing the results achieved or evidence of activities performed during the implementation of the joint venture.

What is the difference between validation and verification?

Verification is confirmation, based on the provision of objective evidence, that specified requirements have been met.

Validation is confirmation, based on the provision of objective evidence, that the requirements for a specific use or application have been fulfilled.

Already the translation of these terms from English provides some food for understanding the difference: verification - verification, validation - giving legal force.

To make it easier to understand, I will immediately give an example of a typical verification: testing a program or testing equipment. Having certain requirements on hand, we conduct a test goods and record whether the requirements are met. The result of verification is the answer to the question "Does it meet the requirements?"

But it is far from always that a product that meets the established requirements can be used in a specific situation. For example, a medicine passed all the required tests and went on sale. Does this mean that it can be used by some specific patient? No, because each patient has its own characteristics and for this particular medicine can be destructive, i.e. someone (the doctor) must confirm: yes, this patient can take this medicine. That is, the physician must perform validation: to give legal force to a specific application.

Or another example. produces pipes intended for burying in the ground, in accordance with some TU (Technical Specifications). The products comply with these TUs, but an order has been received for pipe laying on the seabed. Can pipes corresponding to the existing specifications be used in this case? It is validation that gives the answer to this question.

It is easy to see that another difference is that verification is always performed, but there may be no need for validation. It only appears when requirements arise related to a specific application of the product. If a pharmaceutical plant produces drugs, then it will only check their compliance with the requirements, and will not deal with the problems of using specific drugs by specific patients. Or the same AvtoVAZ.

Thus, we can state the following:

verification - carried out almost always, performed by the method of checking (comparing) the characteristics of the product with the specified requirements, the result is a conclusion about the conformity (or nonconformity) of the product,

Validation - carried out if necessary, performed by analyzing the specified conditions of use and assessing the compliance of product characteristics with these requirements, the result is a conclusion about the possibility of using the product for specific conditions.

ISO 9001 refers to these terms in two places. Let us check if the interpretation I have given is consistent with the content of Sections 7.3.5, 7.3.6 and 7.5.2.

"7.3.5. Design and development verification. Verification should be carried out in accordance with the planned arrangements (clause 7.3.1) to ensure that the design and development output meets the input requirements:".

"7.3.6. Design and development validation. Design and development validation should be carried out in accordance with planned arrangements (clause 7.3.1) to ensure that the resulting product meets the requirements for the specified or intended use, if known. Where as practicable, validation should be completed prior to delivery or use of the product. "

It is easy to see that the interpretation is in full agreement with the text of these sections. At the same time, I would like to draw your attention to the fact that in clause 7.3.5 it is said about the correspondence of weekends data, and in clause 7.3.6 - products. This is essential! This means that the validation is not for the weekend. data, but for products developed for specific conditions. For example, in the activities of the institute for the development of standard projects of residential buildings, validation is not required - only verification. But for the activity on the development of a project for the construction of a residential building according to the same standard design, but in a specific place, validation is already necessary.

"7.5.2. Validation of production and service processes. Company shall confirm all production and service processes, the results of which cannot be verified by means of consistent monitoring or measurement. These include all processes, the deficiencies of which become apparent only after the start of use of the product or after the provision of the service. Validation must demonstrate the ability of these processes to achieve planned results. "

In technology or in the system management quality validation confirms that the requirements of external acquirer or the user of the product, service or system is satisfied. Verification is usually an internal quality management process to ensure compliance with a rule, standard or specification. An easy way to remember difference between validation and verification is that validation confirms that "you created the correct product" and verification confirms that "you created the product as you intended to do it."

Document validation

A valid web document is one that has gone through a similar procedure and has no code comments. The code of a web page must obey certain rules called a specification, which is developed by W3 (www.w3c.org) with the support of the browser developers.

At first glance, it seems that validation is necessary, because we are talking about reducing the number of developers' mistakes and writing "correct" code. In fact, everything is much more complicated, and around validation there is still heated debate about its relevance. In order to objectively reveal this issue, we will further consider the pros and cons of such a check.

Although HTML code has a fairly simple hierarchical structure, it is easy to get confused in the code as the size of the document grows, therefore, it is easy to make a mistake. Browsers, despite obviously incorrect code, will try to render the web page anyway. But since there is no single regulation on how a "crooked" document should be displayed, each browser tries to do it in its own way. This, in turn, leads to the fact that the same document may look different in popular browsers. Correction of obvious mistakes and systematization of the code leads, as a rule, to a stable result.

The days when browser makers added unique features to their product contrary to all standards are beginning to fade into the past. Each new version of the browser increasingly supports the specifications and displays documents with minimal or no errors. Developers of sites that also adhere to the canons of web standards, thus, comply with modern trends in the development of web technologies.

Don't forget about XML (eXtensible Markup Language). This language is becoming the de facto standard for storing data and exchanging information between different applications. XML syntax is more rigid than HTML and does not forgive the slightest mistakes. In a sense, XML is like programming languages ​​in which a program won't compile until the code is debugged. HTML is the first step to learning XML, so by accustoming yourself to write code according to all the rules, it will be easier to move on to the next stage of HTML development.

As it is not surprising, but among web developers there is also a fashion. The current fashion is to create valid documents and display a special icon in the form of a picture that the site complies with the HTML specification. A similar trend has even affected website customers when writing terms of reference for the development of the site, some of them specifically stipulate that the site is made according to web standards.

Compliance with standards has many benefits, which show up in the smallest detail and become noticeable when a certain critical mass is reached. In particular, the amount of code becomes smaller, more compact, and more readable. Accordingly, the loading speed of the site as a whole increases for users.

Sites, of course, are made so that people visit them. It is the visitors who are the measure of the site's work, and they are also interested in the method of obtaining it. The user wants the site to display correctly in his favorite browser, load quickly and contain the materials he needs. Note that there is nothing in this list about the document code and its validity, visitors are simply not interested. Therefore, a completely invalid site, but made with a soul, filled with interesting materials, will attract more visitors than an empty resource, but made according to all the "rules".

Browser developers do not always follow the specification and in some cases interpret the code not according to the given rules, but in their own way. Ultimately, this leads to the fact that a web page that is displayed correctly (that is, the way the developers intended) is displayed in one browser, is displayed with errors in another. Following the specification in such cases is likely to scare off some browser users. For example, Internet Explorer (IE) currently holds the leading position among browsers, but it supports the HTML and CSS specification worse than Firefox and Opera. Obviously, IE users, when visiting a site made according to all standards, but not taking into account the specifics of this browser, will see an unsightly picture.

Site customers, as well as their developers, do not like this situation, so when faced with a choice: standards or a browser, they mostly choose a browser.

It turns out a disappointing picture - there is no particular need to spend time debugging the code to comply with the specification. It is better to devote this time to making the document work without problems in different browsers - this is how web developers mostly think.

XML and XHTML validation

In order to validate the content, you first need to get it. The source (what we have to check against a set of defined rules) can be completely unpredictable:

Remote source.

Let's abstract from the sources mentioned above, because in fact, it doesn't really matter to us where we get the data for validation from: they all ultimately appear as a string. After we have received the string, we need to process it in such a way as to get elements that we can work with in the programming language in which we are programming. First, we need to decide which entities we can turn the input data into. Remember that the basic unit in XML / XHTML is the element. We will make a start from it. In addition to the element, we need a container of elements, which we will call the document.

Every XML / XHTML document consists of a set of elements, and there is always a root element that contains all the other elements. Wait a minute! But this is an ordinary tree! Yes, that's right: we see a tree of elements in front of us. We came to a rather important conclusion: any XML document (and a document in any XML-like language) can be represented as a tree. After that, with this tree, we can perform a very different set of operations: comparison, deletion, rearrangement, traversing (operation of passing through all the nodes of the tree) and others.

XML validation is incomparably simpler than XHTML validation: we only need to make sure that a few requirements are met, which can be done quite safely, given that we have a tree of elements. We will systematize the necessary rules:

The first element in a document is always an XML header declaration of the form, where […] are the XML header attributes;

All elements must be named correctly and must not contain extraneous characters (spaces, for example);

All attributes must be written in the correct form (checked quite simply, with the same regular expression);

The document must contain only one root element;

The nesting of elements must be observed (verification of this statement is achieved by using the stack of elements, with which we check the correspondence of opening and closing elements);

If all of the above rules are followed, then the document is considered a valid XML document. Otherwise, the document contains errors, a list of which the validator can display to the user for review and correction.

XHTML validation is based on XML validation. First, we need to make sure that the document is valid from the XML point of view (that is, the tags are nested, the elements and their attributes are correctly formatted, and others), and only then we impose additional rules. If a document is not valid from an XML point of view, then it is certainly not valid from an XHTML point of view.

To apply any XHTML rules to a document, you first need to describe those rules in such a way that they are easy to obtain and how to stencil them on the document. For validating XHTML documents, rules can be stored in several formats:

DTD documents;

Regardless of the format, the following set of checks is performed:

Checking all used elements in the document for their presence in XHTML (if the element specified in the document does not exist, then a corresponding error is issued);

Checking for the presence of required attributes for the corresponding elements;

Checking the content type of some attributes for compliance with the types specified in the rules;

The content type of the element must match the one specified in the rules;

Since XHTML defines element classes (block and text), the validator must ensure that elements of one class (level) must be correctly nested within elements of another class (level). Similar patterns are also described in the rules.

After executing the specified set of rules, we can talk about whether the document is valid or vice versa: it contains some errors that the validator can indicate to the user.

GMP validation

GMP is a complex integrated solution for design, construction, operation and company production, requires a large financial and labor investment. This has already become a necessary level achieved for a pharmaceutical plant.

In practice, real-world experience and professional advice can help prevent design and equipment errors that can cause huge non-reimbursable losses in investment, time and effort.

For an operating plant: inspection of the plant in relation to the building, general technical condition, product range and related workshops, the condition of equipment, structure and personnel, and knowledge and skills of the personnel about GMP rules, quality control and management documentation, analyzing the degree of compliance with the requirement of the current GMP standard will be overall plan work improvements and schedule. The two sides confirm and begin to fulfill.

For a new facility: plant layout: general plan, project technology, warehousing, quality, production process and gives comments or advice. Checks equipment selection and supplier

Acrecitation in accordance with GMP rules not only needs appropriate facilities and equipment, but also a system of documentation: responsibilities of departments and positions, rules management, rules of operations, rules of quality control, quality standards, records of production batches.

What is EITI Validation?

EITI Validation is a quality assurance mechanism and is an integral part of the EITI process. It has two main functions. First, it stimulates dialogue and learning at the country level. Second, it maintains the level of one global EITI standard in all implementing countries. Validation is not an audit. It is not a repetition of the disclosure and comparison process that are part of the EITI reporting process. Validation has more overarching objectives: with the assistance of stakeholders, it assesses the implementation of the EITI; evaluates the results for compliance with the global standard; and seeks opportunities to strengthen the development of the EITI process.

In addition, validation is a mechanism that is used to determine the status country as a candidate country or country meeting the EITI. Currently 23 countries are candidates. All of these countries meet four entry requirements and are at various stages of EITI implementation. The EITI requires countries to complete the validation process within two years to assess EITI compliance.

Through validation, countries demonstrating compliance with the EITI requirements (or making notable progress towards that goal) gain international recognition for their efforts and achievements. If the validation is incomplete or shows no measurable progress towards achieving EITI Compliance, the EITI Board revokes the Candidate Country status.

The validation process takes place at the international level and is controlled by a multistakeholder group at the state level. validation is set out in the EITI Rules, including guidance on validation.

The first step is to appoint a validator by the multistakeholder group. The EITI Board has compiled a list of accredited EITI Validators, and has prepared guidelines for implementing countries on the appointment of a validator.

The selected validator uses three main documents in its work.

These are:

Country work plan

Validation Requirements and Methods for Measuring Performance, and

Companies questionnaires

Using these documents, the validator meets with the multi-stakeholder group, is involved by the company to reconcile the data disclosed by companies, the government and other key stakeholders (including organizations and the public that are not part of the multi-stakeholder group).

Using this information, the validator completes the report, including:

Concise overview report on progress in implementing the country work plan;

A concise overview report on progress towards the validation schedule targets;

Completed validation schedule;

Overview report on implementation by companies;

Aggregate questionnaires of companies;

Overall assessment of EITI implementation: whether the country is a Candidate, meets the requirements, or there is no measurable progress.

This report first goes to the multistakeholder group, the government and the EITI Board. If these groups agree on a validation report, it is published and the comments are accepted for execution. If there is disagreement about the validation process, then it is considered first at the local level. The EITI Board is only involved in the event of a major disagreement.

Sources of

ru.wikipedia.org Wikipedia - the free encyclopedia

htmlbook.ru For those who make websites

certicom.kiev.ua Certicom

enumerate.ru In search of ordered truth

luxunig.com Pharmaceutical Engineering

Investor encyclopedia. 2013 .

Synonyms:

See what "Validation" is in other dictionaries:

Validation- legalization, approval, legalization, ratification. Dictionary of business terms. Academic.ru. 2001 ... Business glossary

Steps for validating the terminal sterilization process.
Validation - documented actions that, in accordance with the principles of good manufacturing practice, prove that a certain procedure, process, equipment, raw materials, activity or system leads to the expected results with predetermined acceptance criteria (TKP 030-2013. "Good Manufacturing Practice" ).
Process validation is a documented confirmation that a technological process carried out within the established parameters can be carried out efficiently, with reproducible results and leads to the production of a drug that meets the predetermined characteristics of the qualities.
The main documents on the validation of technological processes:
TCP 030-2013 "Good Manufacturing Practice"; TCP "433-2012" "Validation of sterile drug production processes"; TCP "449-2012" "Procedure for the preparation and control of filters for sterilizing filtration"; PDA (Parenteral Drug Association) Technical Report 26 “Sterilizing Filtration of Liquids” (1998); GF RB vol. 1, ed. 2, p. 5.1.
Requirements for the production of sterile drugs:
... Minimal risk of contamination by microorganisms, mechanical particles, pyrogenic substances;
... Production in classified clean rooms and areas with constant monitoring of their degree of pollution.
The main types of technological operations in the production of sterile drugs:
.Production with final sterilization;
.Production under aseptic conditions.
Sterilization is a process that ensures the complete destruction or removal of all viable forms of microorganisms from an object. Final sterilization is a process in which products are sterilized in sealed primary packaging (ampoules, vials, bottles, etc.) and which allows measurements and quantification of lethal effects on microorganisms.
If the product cannot be subjected to final sterilization in packaged form, all or several of the final stages are carried out under aseptic conditions.
Aseptic production is a set of technological processes carried out in aseptic conditions, incl. aseptic filling of containers with products in a controlled environment in which the supply of air, materials, equipment and personnel is regulated so that contamination by microorganisms and mechanical particles does not go beyond specified limits.
Fundamentally different approaches are used to validate 2 types of processes for the manufacture of sterile drugs:
... For drugs undergoing terminal sterilization - validation of the sterilization process
... For drugs produced under aseptic conditions - validation of the sterilizing filtration process and aseptic operations in general.
Validation of the sterilization process (using wet steam):
. development of the sterilization cycle; . certification of sterilization equipment (including using chemical and biological indicators); . study of heat penetration; . study of heat distribution; .performing tests with biological samples (microbiological test using resistant microorganisms); .validation of the process by direct contact of wet steam with the sterilized load; .validation of sterilization and integrity of the sterilizer ventilation filters, etc.

Validation of the sterilizing filtration process in the production of sterile medicines. Filtration, sterilizing filters, requirements for sterilizing filters. Microbiological monitoring of sterilizing filtration conditions.

Validation of the sterilizing filtration process
- filtration systems, including sterilizing level filters to remove microorganisms,
- clean rooms and local areas providing an aseptic environment around these filtration systems.
Filtration is the process of removing viable and / or non-viable particles from a liquid by passing through a filter material.
Filter material is a porous material through which liquid is passed to remove viable or non-viable particles.
Filter - filter material installed in a housing or holder.
Filtration system - a filter equipped with filtration equipment: a sensor, a valve and other elements connected to the assembled filter.
Sterilizing filter - a filter capable of removing microorganisms from the medium in a certain concentration during the filtration process.
Requirements for the characteristics and properties of sterilizing filters:
... ability to retain microorganisms
... lack of ability to sorb drug components
... wide chemical compatibility with various media (drug solutions)
... ability to withstand multiple cycles of regenerating and sterilizing effects
... resistance to mechanical stress
... high performance, etc.
Some of the required characteristics are provided as part of the filter manufacturer's documents.
Properties that are determined by the specifics of use in specific production conditions and with specific drugs must be confirmed (validated) by the user independently:
... Retention capacity of the filter (microbiological testing);
... Integrity;
... Chemical compatibility of the filtered product and the components of the filtration system;
... Adsorption characteristics. Microbiological monitoring of the production environment, control of the number of particles in the air of the sterilizing filtration room.
Monitoring is carried out:
1. In the equipped state (before the start of the sterilizing filtration process, when the equipment and premises are ready for work and there are no personnel):
... control of hands and technological clothing of employees;
... control of materials introduced into the filtration room for sampling;

... 2. In a functioning (operated) state (all room systems and technological equipment function in the prescribed manner in the presence of the required number of personnel performing the process):
... air control;
... control of hands and technological clothes of the operator;
... particle count control.

Checking the retention capacity of sterilizing filters: characteristics of sterilizing filters; microorganisms used to test the retention capacity, biological load, test the antimicrobial properties of drugs against test microorganisms. Carrying out and documenting the procedure.
Retention capacity of sterilizing filter
Sterilizing filter: pore size - 0.2 (0.22) microns.
Why not 0.45 microns?
... In nature, there are small microbial cells with a size of less than 0.5 microns (for example, mycoplasma). In natural populations, such cells are very poorly represented and, on average, account for less than 1% of the "normal" bacterial communities.
... The cells of many bacteria in a depressed state under certain conditions can significantly decrease in size - up to 0.2 - 0.3 microns compared to standard size- 0.5 - 2.0 microns; Therefore, to test the retention capacity of the sterilizing filter, cells of one of the smallest "classic" bacteria, Brevundimonas (Pseudomonas) diminuta, are used:
... The size of cells grown under standard conditions: 0.3 - 0.4 µm (width), 0.6 - 1.0 µm (length).
... The suspension of such cells is considered the international industry standard for microbiological model contaminants to determine the effectiveness of the retention capacity on membranes with a pore diameter of 0.22 μm.
... To validate the sterilizing filtration process, a Brevundimonas (Pseudomonas) diminuta ATCC 19146 culture from the American type culture collection or other control culture collection (NCIMB 11091, CIP 103020) is used. Brevundimonas (Pseudomonas) diminuta Previously belonged to the genus Pseudomonas. Based on the analysis of the structure of cellular proteins, the composition of fatty acids, the sequence of rRNA genes, the ratio of DNA bases and the degree of DNA affinity, they are classified into a separate genus - Brevundimonas.
Characteristic.
... Single mobile aerobic non-spore-forming gram-negative small rods 0.3 - 0.4 µm (width), 0.6 - 1.0 µm (length), with a single polar flagellum.
... Ecology: environment- air, water. Not considered a pathogen, but isolation from clinical material has been reported.
... They need organic growth factors: pantothenate, biotin, cyanocobalamin, methionine or cystine.
... A number of carbohydrates (glucose, lactose, etc.) do not ferment. Oxidase-positive.
... Optimum temperature for growth - 30 -35 ° С Commercial culture preparations:
... A lyophilized microorganism in the form of gelatinous or lyophilized disks (granules, tablets) packed in a vial.
... The bottle contains a desiccant to prevent moisture build-up.
... Storage conditions - from +2 o C to +8 o C (or under other conditions specified by the manual for working with the strain).
In order to be used for the validation of the sterilizing filtration process, the culture is grown on a liquid and agar medium based on casein and soybean hydrolyzate (casein soybean agar - SKA and casein soybean broth - SKB). Colonies on agar medium SKA are round, convex, smooth, glossy, with a smooth edge. The color of the colonies is light beige, sometimes with a grayish-yellow tint. At 24 hours of growth, the colonies become visible, punctate. At 48 hours of growth, the diameter of the colonies is 2.0 - 2.5 mm; for 72 hours of growth - 3.0 - 3.5 mm.
Restoration of culture
... Before starting work with the culture in gelatinous or lyophilized disks (granules, tablets), the closed bottle with the culture is taken out of the refrigerator and kept for 15 - 20 minutes. at room temperature to prevent condensation of water in the bottle upon opening.
... With sterile tweezers, take out one disk (granule, tablet) and place it in 0.5 - 1.0 ml of sterile liquid (isotonic sodium chloride solution, SKB). The bottle is immediately sealed and returned to the storage location (+2 o C - +8 o C).
... The disk (granule, tablet) is suspended, the resulting suspension is inoculated with a sterile microbiological loop with a depleting streak on the SCA in a Petri dish until isolated colonies are obtained. Petri dishes are incubated at 30 - 35 ° C for 48 - 72 hours.
... At the end of the incubation period, the macroscopic and microscopic characteristics are determined.
- Macroscopic characteristics: visual
- Microscopic characteristics: using a light microscope with a calibrated eyepiece micrometer, microorganisms are examined in several fields of view of the microscope to assess their size and location. Additionally, a colored preparation is prepared to confirm belonging to gram-negative bacteria and to identify flagella
- Physiological and biochemical identification.
Maintaining culture
... Isolated colonies are subcultured on a slant agar medium SKA in test tubes and incubated for 48-72 hours at a temperature of 30-35 o C.
... The grown culture is stored at a temperature from +2 o C to +8 o C for no more than 7 days. After the specified storage time has elapsed, the culture is subcultured onto the SKA agar slant medium in test tubes. Incubate and store in the same way.
... The number of passages should not exceed five. A filter is classified as sterilizing if it can withstand a bioburden of Brevundimonas diminuta cells of at least 10 7 CFU / cm 2 of effective filter area and provides a sterile outlet flow.
Bioburden (biological load) - the population of viable microorganisms in the liquid prior to the sterilizing filtration stage. Concentration of Brevundimonas diminuta 10 7 CFU / cm 2 of effective filter area - biological load (provocative load, microbial challenge).
Why 10 7 CFU / cm 2?
The filter can have a number of larger pores than the nominal size and can potentially allow microorganisms to pass through. The likelihood of such transmission increases with increasing bioburden in the media to be filtered.
The actual bioburden of drug solutions to be filtered, as a rule, does not contain microorganisms of a smaller size and in a higher concentration than the provocative load used in validation tests. In most cases, the acceptable concentration of microorganisms in the sterilized liquid is 10 CFU / 100 ml.
Checking the retention capacity of the sterilizing filter is carried out taking into account the real conditions of the drug production:
... By inoculating a suspension of a microorganism into a solution of a specific drug (direct inoculation), since its components can affect both the filter material and the microorganism. It is allowed to use 10% of the actual volume of the standard batch of the drug.
... During the filtration time of the volume of a standard series of drugs
... At a pressure and flow rate corresponding to those in the actual production of drugs
... Taking into account the filtration temperature (if the temperature of the drug solution does not affect the viability of the test microorganism) Direct inoculation of the Brevundimonas diminuta suspension in the drug makes it possible to assess the effect of the drug on the filter material and the microorganism. However, direct inoculation is often impossible due to the antimicrobial properties of the drug against the test microorganism.
Therefore, before carrying out validation tests, it is necessary to determine the presence / absence of the antimicrobial effect of the drug against Brevundimonas diminuta.
Determination of the antimicrobial action of the drug solution against the test microorganism Brevundimonas diminuta
Test conditions:
... The temperature corresponds to the temperature of the filtration of the drug under production conditions (as a rule, room temperature 22 ± 2 ° С)
... The exposure time corresponds to the filtration time of the drug under production conditions
... The number of CFU of the microorganism introduced into the test solutions corresponds to the minimum bioburden on the sterilizing filter - not less than 10 7 CFU / cm 2
Procedure:
1.Preparation of the test and control solutions:
Test solution - a suspension of the test culture is added to the drug solution.
Control solution - a suspension of the test culture is added to a sterile isotonic sodium chloride solution (sterile buffered sodium chloride and peptone solution, pH 7.0).
The number of CFU introduced into the test and control solutions is calculated by the formula: where: N - biological load (CFU) per 1 cm 2 of the filter in an amount of at least 10 7 CFU .; S - filter area cm 2; V 1 - the volume of the tested drug solution, l; V 2 is the volume of the solution passed through the filter in real production conditions or during process validation, l;
Experimental and control solutions, inoculated with a suspension of a microorganism, are kept at a temperature of (22 ± 2) ° С for a time equal to the duration of the sterilizing filtration process of a certain drug under production conditions.
2. Determination of the antimicrobial action of drugs against Brevundimonas diminuta:
... Determine the number of CFU of the microorganism in 1 ml of both solutions at: - zero point (immediately after adding the test microorganism), - midpoint (corresponds to ½ of the drug filtration time) - the end point of filtration (corresponds to the complete filtration of the drug).
Method: a series of serial tenfold dilutions of the test and control samples in the same solvent. From each dilution, 0.1 ml is inoculated into two parallel Petri dishes with agar SCA medium. The dishes are incubated at a temperature of 30-35 ° C for 48-72 hours.
... The number of grown colonies is counted, the number of CFU of Brevundimonas diminuta in 1 ml of the test and control solutions is calculated and the logarithms (lg) of the obtained values ​​are found.
... Determine the difference in logarithms CFU / ml between the control and test solutions: - if the difference in logarithms (lg) is less than 1, the survival of the Brevundimonas diminuta culture and the absence of antimicrobial action of the drug under test conditions are confirmed; - if the difference in logarithms is 1 or more, the drug has an antimicrobial effect.


Conclusion: The drug has no antimicrobial effect
3. Conditions for validation (determination of retention capacity): A. If the drug does not have an antimicrobial effect - during validation, the test microorganism is directly inoculated into the drug solution; B. If the drug has antimicrobial effect, it is necessary:
... Change process conditions:
- reduce the temperature of the solution
- to reduce the exposure time of the "solution-microorganism" system
... Use a model environment:
- reduce the concentration or remove from the drug solution compounds with antimicrobial action
- adjust pH
Requirements for the model environment - to simulate as much as possible the composition and properties of the filtered medium:
- NS
- viscosity
- ionic strength
-osmolarity, etc.
.If the model medium is a solution of one component
- filtering drugs through a membrane filter (worst case), - washing the filter, - filtering a model solution (solvent) that does not contain antimicrobial components.
Methods for preparing a suspension of Brevundimonas diminuta for validating the sterilizing filtration process
1. Use a gelatinous (lyophilized) disk (tablet, granule) or a microbial mass from a slant agar medium (SCA);
2. Aseptically introduced into a liquid medium (SKB);
3. Cultivated with aeration at a temperature of 30-35 ° C
4. Acceptance criterion - the titer at the end of cultivation should be 10 9 - 10 10 CFU / ml;
5. The mode of preparation of the Brevundimonas diminuta suspension for validating the sterilizing filtration process is set in advance
Identification of cell size and homogeneity of a Brevundimonas diminuta suspension? The necessity of the procedure is caused by: - ​​the possibility of the presence of cells in the suspension, the sizes of which exceed the acceptable values; - the ability of cells to aggregate.
? Methods:
... Microscopic examination of Gram-stained preparations: - Light microscope equipped with a calibrated eyepiece micrometer and a high-resolution oil-immersion or dry-air objective. - Consider microorganisms in several fields of view to assess their size and location. ... Filtration through a filter with a pore diameter of 0.45 μm - 10 ml of the prepared suspension is filtered through syringe filter nozzles (pore size 0.45 μm), the filtrate is added to 100 ml of SKB, incubated for 24 - 48 hours at a temperature of 30 - 35 ° C aeration. - After incubation, the presence of growth (visual) indicates the presence of microorganisms in the prepared suspension with a size of up to 0.4 μm in width. - To confirm the presence of Brevundimonas diminuta monocultures in the suspension, microscopic examination of smears stained by the Gram method and a method that allows the identification of flagella is carried out. Registration of the preparation of the Brevundimonas diminuta suspension The procedure for the preparation of the Brevundimonas diminuta suspension for the validation of sterilizing filtration is recorded in the respective protocols.
For example:
... Protocol for the preparation of a suspension of Brevundimonas diminuta;
... Protocol for determining the titer of viable cells in a suspension of Brevundimonas diminuta; ... Protocol for identification of cell size and homogeneity of the Brevundimonas diminuta suspension. Calculation of the volume of the Brevundimonas diminuta suspension providing the required bioburden.
The volume of a bacterial suspension, for example, with a titer of 10 9, required for validating sterilizing filtration (filter retention capacity), is calculated based on the active area of ​​the filter and the minimum load per 1 cm 2 of this area (at least 10 7 CFU / cm 2). For example, if the filter area is 0.8 m2:


Where: 2 7 cm / CFU 10 - the minimum load per 1 cm 2 of the active area of ​​the filter; 2 4 cm 10 8, 0 ⋅ - active area of ​​the filter (ie 0.8 m 2); CFU / ml 10 9 - titer of Brevundimonas diminuta in 1 ml of prepared suspension Thus, to ensure the required minimum load on a filter with an area of ​​0.8 m 2, at least 80 ml of a suspension of Brevundimonas (Pseudomonas) diminuta in a broth based on casein and soybean hydrolyzate is required with a titer of 10 9 CFU / ml
Calculation of the bacterial (pre-sterilization) load of the drug solution (model solution) - 80 ml of the prepared suspension of Brevundimonas diminuta with a content of 10 9 CFU in 1 ml is introduced into the drug solution (10% V), while the minimum load per 1 cm 2 of the active filter area is 10 7 CFU / cm 2 with a filter area of ​​0.8 m 2. - The total load on the filter with an area of ​​0.8 m 2 is: 80 ml · 10 9 CFU / ml = 8 · 10 10 CFU. - (10% V) l of the prepared suspension of Brevundimonas diminuta in a drug solution contains 8 10 10 CFU of the culture of Brevundimonas diminuta
- The number of CFU in 1 ml of the prepared solution - the bacterial (pre-sterilization) load of the drug solution (model solution) - is:

where: ((10% .V) .10 3 ml) - the volume of the drug solution or model solution in ml
Method for determination of pre-sterilization load (titer of viable cells in a suspension of Brevundimonas diminuta)
- Method of tenfold dilutions in sterile 0.9% sodium chloride solution. From test tubes with tenfold dilutions of the culture suspension (10 -7, 10 -8 and 10 -9), inoculations of 0.1 ml of the suspension are made in Petri dishes with agar based on hydrolyzate of casein and soybeans. For each dilution, use at least 2 Petri dishes. The dishes are incubated at a temperature of 30 - 35 ° C for 48 - 72 hours, after which the results are recorded. - In parallel, control the purity of the culture. -The number of viable cells in 1 ml of the initial suspension is calculated as follows: x = a · 10ⁿ · 10, where x is the cell titer (CFU / ml), a is the average number of grown colonies in a Petri dish for each dilution, n is the degree of the corresponding dilution , 10 is the conversion factor for converting 0.1 ml to 1 ml. The resulting value must match the calculated one.
Validation (determination of retention capacity)
1. Preparation of the tested drug solution and / or model solution (10% of V); 2. Preparation of a suspension of Brevundimonas diminuta with a titer of at least 10 9 CFU / ml determination of the cell size and homogeneity of the suspension;
3. Inoculation of a drug solution or a model solution with a suspension of Brevundimonas diminuta, taking into account the provision of a bioburden of at least 10 7 CFU / cm 2 of the useful area of ​​the sterilizing filter;
4. Determination of pre-sterilization bioburden;
5. Carrying out the process of sterilizing filtration;
6. Control of the sterility of the solution after sterilizing filtration by inoculating the sample into a liquid nutrient medium (SKB).
Acceptance criterion: Filtrates must be sterile.
7. Validation is carried out on three series of drugs (model solutions).
Documenting the procedure:
... Development of a validation plan that contains:
- a detailed statement of the goal and general strategy,
- characteristics of the object being validated,
- the composition of the validation team, duties and responsibilities for the stages of validation,
- conditions for validation,
- monitored indicators and acceptance criteria,
- the procedure for conducting tests,
- list of reports and protocols.
... Writing a written report on the validation: in accordance with the validation protocol.

Lecture, abstract. Validation of technological processes. Types of technological operations in the production of sterile drugs and approaches to their validation. - concept and types. Classification, essence and features. 2018-2019.

Book table of contents open close

1. Pharmaceutical microbiology. The subject and objectives of pharmaceutical microbiology.
2. Pharmacy and pharmaceuticals: history of origin and development.
3. Medicinal product: definition, classification.
4. Composition of medicines | pharmaceutical substance, excipient.
5. Original and generic medicines. The name of the medicinal products.