Validation, approval, legalization, ratification
(common civil law);

The process of determining how accurately a model represents given real-world entities from a potential user's perspective.
(system Programming);

A procedure that provides 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 established parameters) is repeatable and leads to the expected results in the production of an intermediate or finished product of the required quality; validation of analytical methods consists of determining: accuracy, reproducibility, sensitivity, stability (interlaboratory reproducibility), linearity and other metrological characteristics
(GMP - Good Manufacturing Practice, is a mandatory requirement in the production of medicines ).

In relation to quality management systems according to ISO 9000 series standards:

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

Validation- confirmation by examination and provision of objective evidence that the specific requirements intended for a particular application are met.
Notes:
1. In design and development, approval means an examination of the product to determine compliance with consumer needs.
2. Approval is usually carried out on final products under specified operating conditions. It may be necessary at earlier stages.
3. The term "approved" is used to indicate the appropriate status.
4. Multiple approvals may be made if different uses are intended.
(ISO 8402:1994, clause 2.18)

Let's analyze the requirements of the ISO 9001 standard:
ISO 9001, clause 7.3.6: Validation of the design and development must be carried out in accordance with the planned activities to ensure that the resulting product meets the requirements for its intended or intended use.
ISO 9001, clause 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 has been used or the service has been provided. Validation must demonstrate the ability of these processes to achieve intended results.
ISO 9000, note 3 clause 3.4.1: A process in which confirming the conformity of the final product is difficult or economically impractical is often referred to as " special process ".

Generally accepted requirements for special production processes, ensuring their validation:
1) certification of the production process (technology, methodology, work instructions...)
2) certification 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) personnel certification (qualification requirements for welders or welding robot operators, adjusters, service companies...)
with appropriate documentary evidence. ( A. Oreshin)

Specialist. the process (SP) must be under controlled conditions.
Controlled conditions include:
- availability of information describing the characteristics of products and joint ventures;
- availability of regulatory, design and technological documentation;
- use of suitable equipment;
- availability and use of control and measurement equipment;
- carrying out monitoring, measurements and tests;
- carrying out activities to implement the joint venture;
- availability of qualified and certified personnel implementing the joint venture;
- re-validation;
- availability of records containing results achieved or evidence of activities performed during the implementation of the joint venture. ( V. Zolotukhin)

Validation, verification, special process

How is validation different from verification?
The ISO 9000 standard defines these terms as follows:
"Verification- confirmation, based on the provision of objective evidence, that the specified requirements have been met."
"Validation- confirmation, based on the provision of objective evidence, that the requirements intended for a particular use or application are fulfilled."
It would seem that the definitions almost coincide, and if not completely, then to a significant extent. And, nevertheless, verification and validation are fundamentally different actions.
Let's figure it out.
Already the translation from English of these terms provides some food for understanding the difference: verification - verification, validation - giving legal force.
To make it easier to understand, I’ll 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 verification result is the answer to the question “Does the product meet the requirements?”
But not always a product that meets the established requirements can be used in a specific situation. For example, the medicine passed all the required tests and went on sale. Does this mean that it can be used by any specific patient? No, because Each patient has his own characteristics and specifically for this, the medicine can be destructive, i.e. someone (the doctor) must confirm: yes, this patient can take this medicine. That is, the doctor must perform validation: give legal validity to a specific application.
Or another example. The company produces pipes intended for laying in the ground in accordance with certain specifications (Technical Conditions). The products comply with these specifications, but an order has been received that involves laying pipes along the seabed. Can pipes that comply with existing specifications be used in this case? It is validation that provides 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 appears only when requirements arise related to a specific product application. If a pharmaceutical plant produces drugs, 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, the following can be stated:
verification - is almost always carried out, performed by checking (comparing) the characteristics of products with specified requirements, the result is a conclusion about the conformity (or non-conformity) 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.
The ISO 9001 standard refers to these terms in two places. Let's check whether my interpretation corresponds to the content of sections 7.3.5, 7.3.6 and 7.5.2.
"7.3.5. Verification of design and development. Verification shall be carried out in accordance with the planned activities (clause 7.3.1) to ensure that the output of the design and development meets the input requirements:."
"7.3.6 Design and Development Validation Design and development validation shall be carried out in accordance with the planned activities (clause 7.3.1) to ensure that the resulting product meets the requirements for its specified or intended use, if known. Where it is practicable that validation should be completed before delivery or use of the product."
It is easy to see that my interpretation is in full agreement with the text of these sections. At the same time, I would like to draw attention to the fact that clause 7.3.5 talks about compliance of output data, and clause 7.3.6 - products. This is significant! This means that validation is not carried out for output data, but for products developed for specific conditions. For example, in the activities of the institute for the development of standard designs for residential buildings, validation is not required - only verification. But for the activity of developing a project for the construction of a residential building according to the same standard project, but in a specific location, validation is already necessary.
"7.5.2 Validation of production and service processes. The organization shall validate all production and service processes the results of which cannot be verified through consistent monitoring or measurement. This includes all processes in which deficiencies become apparent only after the product has been used or the service has been provided. Validation must demonstrate the ability of these processes to achieve intended results."
There are no discrepancies here either. But it should be noted that in cases falling under clause 7.5.2, product characteristics cannot be measured directly and their assessment will be carried out indirectly (for more details, see the lecture on special processes).
Question: What are the activities of the Quality Control Department?
Answer: This is verification.
Question: What are the activities of auditors?
Answer: to verification.
Question: what function does the signer of the act of commissioning an object (service, etc.) perform?
Answer: It does the validation.

Defining a Special Process

Criteria for classifying a process as “special”
Of course, those who say that the standard does not directly define the term “special process” are right. This phrase appears in Note 3, clause 3.4.1 of ISO 9000 " 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, here the main sign of “specialty” is the difficulty (problematic) of confirming compliance. Of course, such a criterion can hardly be considered unambiguous, since the degree of difficulty beyond which the process can already be considered “special” is unclear.
On the other hand, clause 7.5.2 of the ISO 9001 standard establishes the requirement: " The organization shall validate all production and service processes the results of which 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 even included in the ISO 9001 standard? Or in other words: what is the practical significance of process confirmation (validation) for quality management?
The purpose of the quality management system (according to ISO 9001) is to ensure stable product quality, understood as compliance with consumer 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 to do 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 in, which says that such processes must be “validated” to “demonstrate the ability of these processes to achieve the intended results.” Those. If you can't verify the result, then confirm the "correctness" of the process, based on the assumption that the "correct" process produces the "correct" result.
There is an obvious commonality between the provisions of Note 3, clause 3.4.1 of ISO 9000 and clause 7.5.2 of the ISO 9001 standard: both relate to confirmation of product conformity. But there is 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. we are talking about "impossibility".
So can the processes for which the requirements are established in clause 7.5.2 be considered those very “special” processes? I suppose yes, because... "impossibility" is the extreme degree of "difficulty".
The practical significance of making a decision to classify a process as “ordinary” or “special”
Classifying (or not classifying) a process as “special” is of practical importance and is carried out as part of the process planning provided for in section 7.1 of the ISO 9001 standard.
The fact is that, as I will try to show below, the “ordinary” and “special” processes are constructed in different ways, and this difference in construction is explained by different methods for determining the effectiveness of the process. Without going into details, we can say that the effectiveness of a “regular” process is assessed by the compliance of the result with the specified requirements, and the effectiveness of a “special” process is assessed by the compliance of the actions performed within the process with the established technology. In other words, we will call a “ordinary” process effective when its output meets the specified requirements, and “special” - when the technology for obtaining the output corresponds to the established one. Therefore, when building a “usual” process, we must include operations for monitoring compliance with the requirements of results at the intermediate and final stages of production, based on 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 technology compliance.
Can the process of providing a service be considered special?
Clause 7.5.2 contains the instruction: " To them["special"] Processes include all processes the shortcomings of which become apparent only after the product has been used or 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 as it relates to services.
Firstly, I would like to draw attention to the fact that the provision speaks about the shortcomings of the process, not the product.
Secondly, I would like to show with the following two block diagrams the fundamental difference between the process of producing material products and the process of producing services.

Now is the time to define what it is service. By service I will understand 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 widely held position that when a service is provided, its production and consumption coincide in time.
Reflection on the nature of the service delivery process leads us to understand that
- the result of the service provision process is the consumed service, i.e. a service whose production and consumption process has completed,
- the consumer is a participant in the process of providing the service (is “inside” the process),
- an attempt to move the consumption of a service beyond the boundaries of the service provision process leads to the “disappearance” of the output and, accordingly, the process itself.
The last provision indicates that at point A (second figure) there is no service yet 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 [result]” is applicable to the service delivery process.
Obviously yes. The same telecommunications services give us the following example: a channel is organized for the client through which the client’s signal is sent and all agreed upon parameters are monitored. And after completion of the service, based on monitoring and measurement data, we will be able to say whether the process was effective or not. Here is the key point: to establish the effectiveness of the process, we will not analyze records of the execution (or non-execution) of certain actions, or the compliance of these actions with those planned, but we will analyze records of 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 most obviously tells us that the service delivery process in question cannot in any way be classified as special.

Examples demonstrating the practical application of the discussed criteria
To support our arguments with examples, let's start with services.
Situation one. There is a forwarding company that provides delivery services. She decides to include furniture in the delivered goods. It is necessary to plan the process, which necessitates the need to understand whether the process will be "regular" or "special". Main parameters of the service: accuracy of delivery (time and place), safety of the cargo. Can these parameters be assessed (measured)? Of course, there are no obstacles to that. Can we confirm the effectiveness of the process based on evaluation (measurement) data? Without any doubts. Conclusion is a “normal” process.
Situation two. The same forwarding office 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 the parcel fell into a swamp, or hung from a tree) or safety. And in the absence of data on the result, the effectiveness of the process will be judged by the implementation of the technology: the bowstring was pulled with the required force, the elevation angle was set to the desired one, the azimuth was set accurately, a correction for the wind was made, etc. - i.e. did everything to get the desired result. Conclusion - the process is "special".
Situation three. We produce products - well, let's say, household bicycles - and we have the opportunity at each stage of production to measure the parameters of parts or assemblies and monitor their compliance with the requirements. Before we give 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 would classify such a process as ordinary.
Situation four. At NASA's request, we are making a bicycle to ride on Mars. In this case, one of the requirements states: the connections must have a special lubricant, after applying which the assembly must be completed and the product must be placed in a sealed container with a special gas environment. Obviously, such a requirement deprives us of the opportunity to perform a final inspection of the bike and we must recognize it as “special” when planning the process. In this case, complying with 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 of the production cycle based on these records that everything was done “as it should.” This confirmation, in turn, will serve as evidence (albeit indirect) that the result of the process meets the requirements.
It is common to see statements like “welding is a special process” or “painting is a special process.” In my opinion, such statements are not entirely correct.
We will assume that the result of welding is a weld seam. We have a regular order: pipes for an onshore gas pipeline and all the requirements are normal. What prevents you from checking all seam parameters using the current diagnostic technology? Probably nothing. Those. We can easily establish (confirm) the compliance of the result with the requirements of “successive monitoring or measurements.” But then another order came: we need to make a seam that should immediately break under a certain load. Well, how do we confirm compliance with this requirement? The process immediately turned from “ordinary” into “special”.
And hence the conclusion: the process can be either “ordinary” or “special” - depending on the requirements for the result. Just as an “always special” process can become “ordinary” with the advent of new technologies and diagnostic devices.
And this is confirmed by the fact that the section. 7.1, speaking about process planning, emphasizes: “... for specific products " (see paragraphs b and c).
So, summary:
- “ordinary” and “special” processes differ in the methods of confirming the conformity of the result, and therefore, in order to correctly construct 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 sign “impossibility of confirming the conformity of a product by methods of measuring and monitoring its parameters” (i.e., inability to confirm the effectiveness of the process by methods of measuring and monitoring the result),
- the application of which clearly shows the inconsistency of the widespread belief: all processes for providing services are “special”. (A. Gorbunov)

Pharmaceutical industry in the EU, in accordance with the principles of GMP, 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 works correctly and actually produces the expected results. Sometimes the concept of validation is expanded to include the concept of qualification.
Validation consists of the following processes:
- qualification of design documentation (Design Qualification - DQ) - verification of the description and development of the system;
- installation qualification (Installation Qualification - IQ) - checking the ability of the system infrastructure to support the operation of the system;
- Operational Qualification (OQ) - checking the ability to function according to the requirements;
- Performance Qualification (PQ) - checking the company's ability to use the system.

METHODOLOGICAL INSTRUCTIONS

FOR PRACTICAL (SEMINARS)

CLASSES

Course 4

Discipline: FUNDAMENTALS OF DESIGN AND PRODUCTION EQUIPMENT

Compiled by:

Murzagalieva E.T.

Almaty, 2017

Practical lesson No. 11

Process validation and qualification of production equipment.

Process Validation is a procedure for documenting that a specific process (such as the production of pharmaceutical products) can, with a high degree of assurance, produce a product that meets established quality indicators (specifications).

Validation is an integral part of a carefully planned, consistent product/process development program

Validation- these are actions that, in accordance with the principles of good manufacturing practice, demonstrate that a particular procedure, process, equipment, raw material, activity or system actually produces the expected results (EU GMP guidance).

Qualification is the process of documenting that the design of a production site (engineering system, equipment, warehouse, etc.) complies with the design assignment (User Requirements Specification, URS) and GMP requirements.

Scope of application - objects of qualification and validation:

Technical systems

Premises

Equipment

Engineering (technical) systems for ensuring the functioning of production

Technological process

Quality Control Techniques

Cleaning Methods

Approaches:

New technological processes

Validation when making changes

Planned critical revalidation

Types of validation:

Prospective Validation

o before the sale of manufactured products

Related Validation

o during serial production of products

Retrospective Validation

o processes have already been running for some time

Main tasks of validation:

Confirmation of the correctness of the regulated parameters of technological processes - ensuring product quality during the execution of technological process operations;

Confirmation of the correctness of instructions for the implementation of technical process operations (compliance with the capabilities and purpose of the equipment);

Confirmation of the equipment’s ability to ensure compliance with all parameters of technical processes and product quality;

Confirmation of the ability (ability) of personnel to ensure compliance (compliance) with regulated requirements;

Reproducibility (reproduction accuracy) of technical process parameters and at the same time ensuring the necessary quality indicators.

General requirements and principles:

Technical facilities (premises, equipment, systems) are qualified

Analytical methods are validated

The process is properly designed and tested

Personnel who take part in validation tests are trained

Changes are managed

Ensuring the frequency of assessment of technical means, systems, equipment, processes to confirm their proper functioning

Qualification of equipment and engineering systems provides guarantees that the equipment and engineering systems correspond to their functional purpose, stably support the technological process parameters we require and do not introduce any contamination into the product. The scope of qualification is established based on the criticality of the infrastructure facility.

Performing critical cleaning procedures is important to achieve the required quality of equipment surfaces and levels of cleanliness, which in turn avoids product contamination. In addition, the results of cleaning validation make it possible to abandon laboratory monitoring of washouts and rinsing waters after each cleaning cycle, which significantly saves time when switching to the production of another drug.

The use of validation in the pharmaceutical industry stemmed from borrowed experience from the aerospace industry in 1960. It was first used to validate sterilization processes and the production of solid dosage forms. Shortly after this, almost all drug production processes were subject to validation.

1987 - FDA releases guidance on process validation.

At the moment, validation is a mandatory part of GMP.

The validation process can be compared to legal practice - just as a lawyer proves his client is right, so validation engineers, using research results, prove the suitability of a production facility to produce high-quality products.

Validation. Special cases:

• Qualification - activities that confirm that a particular piece of equipment operates correctly and actually produces the expected results. (EU GMP guidelines).
• Validation of methods (Analytical Validation, AV) - documented confirmation that the approved control method is suitable for use in the production and quality control of medicines.
• Cleaning Validation (CV) is documented evidence that an approved cleaning procedure provides the level of equipment cleanliness required for the production of medicinal products.
• Process Validation (PV) is documentary evidence that a process, performed within established parameters, operates efficiently and reproducibly, producing a medicinal product that meets all specified product and quality requirements.

As we see, qualification is a narrower concept, in contrast to validation, and defines a separate direction that relates to testing the parameters of engineering systems, production facilities, technological and laboratory equipment, and other technical means for compliance with the requirements of GMP and other regulatory documents governing safe production of medicines of the required quality.

Qualification stages:

• Project qualification (Design Qualification, DQ) is the process of documenting that the production design (engineering system, equipment, warehouse, etc.) complies with the design assignment (User Requirements Specification, URS) and GMP requirements.
• Installation Qualification (IQ) - documentary evidence that the installation of premises, systems and equipment (installed or modified) was carried out in accordance with the design and other technical documentation.
• Operation Qualification (OQ) - Documented evidence that premises, systems and equipment (installed or modified) function in accordance with specified requirements, in all modes of operation.
• Performance Qualification (PQ) is documentary evidence that the premises, systems and equipment as a whole operate efficiently and reproducibly in accordance with industrial regulations, technological instructions and product specifications.

Types of process validation:

• Prospective validation is validation performed before the start of mass production of products intended for sale.
• Concurrent validation - validation that is carried out during the serial production of products intended for sale.
• Retrospective validation is the certification of the serial production process of a sold product, based on data obtained on the production and control of product batches.
• Re-validation - Repeating the initial process validation to ensure that changes to the process (equipment) made in accordance with the change control procedure do not impair process performance and product quality.

Repeated validation (revalidation) is carried out:

• in a planned manner within the time limits established by the enterprise in the Validation Report.
• before resumption of production in cases of changes in documentation and/or production conditions that may affect the quality of the semi-product and finished product. The scope of validation work is determined by the enterprise based on the changes made.

Based on the above terminology, it is clear that the concepts of “Prospective”, “Concurrent” and “Retrospective” validation refer only to the production processes of products intended for sale. However, the use of these terms when organizing and planning work on the validation of other types of processes has already been given and is effectively used by validation services.

Validation planning

GMP requirements require manufacturers to determine what validation work is necessary to demonstrate control of critical aspects of their specific operations. Significant changes made to facilities, equipment and processes that may affect product quality must be validated. A risk-based approach should be used to determine the scope and scope of validation.

All validation activities should be planned. The key elements of the validation program should be clearly defined and documented in the Validation Master Plan (VMP) or relevant documents (EU GMP guidelines).

A distinctive feature of validation work is the need for joint work of specialists in various fields: pharmacists, technologists, engineers, metrologists, etc. As a rule, validation work takes place under strict time constraints. Conducting validation studies is expensive, since this requires the involvement of highly qualified specialists, the purchase of specific equipment, etc.

All these factors require proper planning and proper organization for clear and consistent implementation of validation work.

Validation Policy

The manufacturer's overall policy regarding the intent and approach to validation, including the validation of processes, cleaning procedures, analytical methods, in-process testing procedures, computerized systems, and those responsible for developing, validating, approving, and documenting each shall be documented. validation stage.

Critical parameters/characteristics should generally be determined at the design stage or based on previous experience; The ranges of these critical parameters/characteristics required for reproducible operations should also be determined. In this case it is necessary:

• determine the critical characteristics of the API as a product;
• identify process parameters that may influence the critical quality characteristics of the API;
• establish a range for each critical process parameter that is expected to be used in batch production and process control.

Validation should cover those operations that are identified as critical to the quality and purity of the API (EU GMP guidelines).

Validation is a broad and general concept aimed at demonstrating the degree of quality assurance of manufactured products by testing technological processes, engineering systems, equipment, production facilities, control methods, etc. This process is logically interconnected and echoes many fundamental sciences (chemistry, physics, mathematics, etc.) etc.) which allow us to consider in more detail the properties of medicines, the raw materials from which they are made, the processing stages before obtaining the finished product, and help to identify and evaluate the most critical operations, inconsistencies in which will lead to irreparable consequences, thereby preventing the appearance of low-quality products on the market medicine.

Literature:

Main:

1. Fundamentals of design of chemical production: Textbook for universities / Ed. A. I. Mikhailichenko. – M.: ICC “Akademkniga” 2010. – 371 p.

2. Clean room technology. Fundamentals of design, testing and operation / V. White. - Publishing house "Cleanroom", 2008.

3. Design of clean rooms. Ed. V. White. Per. from English - M.: ed. "Cleanroom", 2004. - 360 pages.

4. Fundamentals of design of chemical production: Textbook. allowance / Dvoretsky S.I., Kormiltsin G.S., Kalinin V.F. - M.: Publishing house "Machine Building-1". 2005. 280 p.

5. Rationing of pharmaceutical production. Ensuring product quality / V.V. Beregovykh, A.P. Meshkovsky. – M.: Publishing house CJSC “Information and Publishing Agency “Remedium”, 2001. – 527 p.

Additional:

1. Architectural design: a textbook for students. avg. prof. education / M. I. Tosunova, M. M. Gavrilova. – 4th ed., revised. and additional – M.: Publishing center “Academy”, 2009. – 336 p.

2. Large reference book on the structures and materials of modern buildings, 2006. - 620 p.

3. STRC 1617. Good Manufacturing Practice (GMP).

4. Spitsky O.R., Aleksandrov O.V. GEP - Good Engineering Practice. Recipe. - No. 2 (88). - 2013. - P. 7-14.

5. Spitsky O.R. Good Engineering Practice (GEP) as a system. engineering management. Pharmaceutical industry. - No. 6(29). - 2011. - P. 50-53.

6. Allen E., Iano J. Fundamentals of Building Construction: Materials and Methods, 6th Edition. - Hoboken, New Jersey: John Wiley & Sons, Inc., 2014. - XVI, 1007 p.

7. Hicks Tyler G. Handbook of Civil Engineering Calculations, Publisher: McGraw-Hill Publication: 2007, English Isbn: 9780071472937 Pages: 840

The concepts that we will thoroughly analyze are quite often encountered both in everyday life and in specialized literature and professional activities. Many people want to know, verification and validation - what is it in simple words? What is the difference between these terms? Let's think together.

Validation and verification - what is it in simple words?

Both concepts are associated with testing a product and ensuring its quality. If we speak in simple language, we will derive the following:

• Validation is the manufacturer’s guaranteed confidence that he has created the product according to all necessary standards.
• Verification - helps to ensure that the product meets all initially specified requirements for it.

Telling in simple words that this is verification and validation, you need to focus on the following facts:

• What matters most to the consumer is validation - making sure they are getting the right product to meet their requirements.
• For the manufacturer, verification will be more valuable - confirmation that the product he is sending for sale meets all necessary standards and norms.

One more meaning

We will also look at the difference between the concepts of “verification” and “validation” in testing. After all, by and large they are related to international requirements for verification and acceptance of technologies and various products.

However, at the same time, words have become an integral part of the lives of Internet users. For example, when registering with payment systems such as Qiwi and Yandex.Money, you must go through a verification process. In this case, this means verifying the authenticity of the specified data about yourself, identifying you with the system.

And those who actively use social networks (VKontakte, Odnoklassniki, etc.) sooner or later see a window in front of them asking them to undergo validation. This is the same verification of the truth of the data you entered. For example, an SMS with a code is sent to the phone linked to your account, which you need to type in a certain field to confirm that you are the owner of the specified number.

Thus, in this case it is difficult to distinguish the difference between validation and verification. Both of these, in essence, are a check to ensure that the data corresponds to reality. We would also like to point out the fact that validation/verification is successfully used by the developers of various viruses in order to lure personal information from you. Why such data should be entered on reliable resources, from a computer protected by a modern, high-quality antivirus.

Definition of ISO 9000:2000 standard

To explain in simple words that this is verification and validation, the description of these terms given in ISO documents (ISO - International Organization for Standardization) will help. Here we see the following:

• Verification is confirmation, based on objective facts provided, that established standards have been met.
• Validation is confirmation, based on objective evidence provided, that established standards for a specific application have been met.

From these definitions the difference between validation and verification already follows:

• The first procedure is carried out only when necessary. The product is analyzed under specified operating conditions. The result will be a verdict: is it possible to use it in this situation.
• The second procedure is almost mandatory. This is a test to ensure that the product meets requirements that will be relevant under any conditions, under any use.

Other definitions of verification

A number of common definitions of the concepts under consideration will help us understand the topic. Here are the verification characteristics:

• Confirmation of compliance of the released goods or product with certain standards.
• Almost a mandatory procedure; comparison of the characteristics of a manufactured unit with a set of specified requirements. The result is a verdict of compliance or non-compliance with the latter.
• Proclamation of confirmation that the established standards for the product have been met.
• In simple words, a product has been created that meets the required standards.

Other definitions of validation

Let's now look at the definitions of validation:

• A practical determination of how well a particular product meets the expectations of its direct users.
• A procedure that is performed when necessary. This is a common analysis of given conditions and an assessment of the performance of a product regarding its operation in a given environment. The result is a conclusion about the possibility of using a product or invention in a certain area.
• Confirmation of compliance with the requirements of the standards system, the customer, the direct user, etc.
• In simple words, the right product has been created to satisfy the consumer.

Differences based on translation

To determine the difference between validation and verification, turning to the translation of these words that have English roots will also help:

• Verification - some kind of verification.
• Validation - giving something legal force.

Even from this it follows that verification precedes validation and is not final. The final verdict on the product, which has legal force, is given by the latter.

Differences between verification and validation in comparison

In a comparative table it is easier to identify the differences between these somewhat similar terms.

Verification	Validation
Are we making the products right?	Have we produced the right product?
Has all functionality been implemented?	Was the functionality implemented correctly?
Verification precedes validation: it includes a complete check of the correctness of spelling, production and other creation.	It happens after verification - the quality of the manufactured product.
Conducted by developers.	Conducted by testers.
Statistical type of analysis: comparison with established product requirements.	Dynamic type of analysis: the product is tested in operation to determine its compliance with regulations.
Objective assessment: made on the basis of compliance with certain standards.	Subjective assessment: personal assessment given by a tester.

Let's think a little more about how validation differs from verification in the next section.

Key differences between concepts

So, let's dot the i's. Verification is any testing that a product goes through. Checking the correctness of its production technology, as well as the quality of the product. Validation is a concept closer to certification. This is compliance with some specific, rather than general, requirements. How good the product is not in general, but specifically for a specific consumer, customer or given conditions.

It can also be noted that verification is paper, theoretical testing of a technology or product. Validation is a real, physical check, carried out in practice, under specific conditions.

If a product has passed verification, it means that it meets some specified technological requirements. If validation is successfully completed, it turns out that in practice it is also applicable without any complaints. From this we can conclude that the latter concept is somewhat more important and indicative than the first.

Verification examples

Let's look at specific examples to reinforce the difference between these concepts in our heads.

A pharmaceutical plant tests drugs to ensure they meet specific requirements. When entering into production, their safety for the patient in certain doses, the absence of a placebo effect, the absence of the possibility of harmful addiction, etc. are established. Thus, the drug has passed verification. And in this case, validation is carried out by the attending doctor: he determines whether the medicine will help a particular patient, whether its use will not lead to a risk to the life and health of this person, etc.

Let's look at the example of a bicycle. We check whether there is a steering wheel, seat, chains, wheels, brake system, etc. Everything is in place? Verification passed!

Validation Examples

Now examples of how validation differs from verification.

An enterprise produces universal pipes in accordance with certain requirements. A question comes from a customer: is it possible to lay this product along the bottom of the sea? The manufacturer must validate its pipes in accordance with the proposed conditions in order to objectively answer this question.

Using the example of the same bicycle, it is also very easy to consider validation. Can you ride the device? Can I slow down? Can I turn right or left? Change speed? If everything is possible, the validation is passed. They couldn’t brake, the seat fell, the steering wheel became loose - alas, the bike did not undergo this procedure.

So we looked at the concepts of “verification” and “validation”, trying to express everything in simple language. We hope that this will help you clearly see the difference between them and the features of each.

Table of Contents

Guidance on process validation for the production of medicinal products for human use.

Approved on September 26, 2017 (effective from March 29, 2018 (6 months from date of publication)

1. Introduction

1. These Guidelines are the rules for documenting the results of confirmation that the manufacturing process, carried out within established parameters, effectively and reproducibly produces a medicinal product that meets established specifications and quality indicators for their presentation in the registration dossier of the medicinal product.
2. The introduction of continuous process verification defines an alternative approach to process validation based on continuous monitoring of the production process. This approach is based on knowledge of the product and process gained during its development and/or experience from previous production. Continuous process verification can be used in both traditional and advanced approaches to pharmaceutical development. Continuous monitoring and/or control methods may be used to evaluate the process. It is assumed that the combination of provisions contained in the pharmaceutical development guidelines adopted by the Eurasian Economic Commission and in these Guidelines covers all critical stages of the technological process, subject to inclusion in the registration dossier of a medicinal product for medical use, in accordance with Appendix No. 1 to the Rules for registration and examination of medicinal products for medical use, approved by the Decision of the Council of the Eurasian Economic Commission of November 3, 2016 No. 78 (hereinafter referred to as the registration dossier, Registration Rules and examination).

1. Process validation should not be treated as a one-time event. The process life cycle approach to validation involves product and process development, validation of the industrial scale manufacturing process, and maintenance of the process in a controlled state during routine industrial production.

2. Scope of application

1. These Guidelines define the composition of process validation information to be submitted when registering a medicinal product of a chemical nature for medical use. The general principles regarding validation also apply to active pharmaceutical ingredients. It is generally not required to provide information on process validation for the production of non-sterile pharmaceutical substances in the registration dossier. Requirements for validation of the production of active pharmaceutical ingredients are set out in more detail in the guidance of the International Council for Harmonization of Technical Requirements for the Registration of Medicinal Products for Human Use“Development and production of pharmaceutical substances (chemicals and biotechnological (biological) compounds)” (ICH Q11). The principles contained in these Guidelines apply to biological medicinal products. Due to the inherent complexity and variability of biological substances, process validation for the manufacture of such medicinal products must be considered on a case-by-case basis.

1. The information required in accordance with these Guidelines is presented in the registration dossier at the time of submitting an application for registration of a medicinal product to the authorized body of a member state of the Eurasian Economic Union in the field of circulation of medicines (hereinafter referred to as the authorized body, member state).
2. Validation of the manufacturing process in accordance with these Guidelines is considered the second stage of the process life cycle. The first stage (process development) is discussed in the pharmaceutical development guidelines, the third stage (ongoing process verification) is discussed in Appendix No. 15 to the Rules of Good Manufacturing Practice of the Eurasian Economic Union, approved by the Decision of the Council of the Eurasian Economic Commission of November 3, 2016 No. 77 (hereinafter — Rules of good manufacturing practice).

3. Definitions

1. For the purposes of this Guide, terms are used that mean the following:

"process validation"— documented confirmation that the production process,performed within established parameters, effectively and reproducibly ensures the production of a medicinal product that meets pre-established specifications and quality indicators;

"product life cycle") - all stages of a product’s life from initial development, being in circulation and until the product ceases to exist;

“exploration of extreme options (bracketing)” (bracketing)— a scientific and risk-based approach set out in a process validation plan that justifies the possibility of testing only batches with extreme values ​​of certain factors, for example, with a certain dosage, batch size and (or) packaging capacity during process validation. This approach assumes that the validation of any intermediate values ​​of factors is represented by the validation of extreme values. An extreme variation study may be applicable for a range of strengths to be validated if those strengths are the same or very similar in composition, for example for tablets produced with different compression forces from a similar granulate, or for a range of capsules with different capacities filled with the same composition of contents. Extreme case studies can be applied to containers with different capacities or different filling volumes of the same container-closure system;

“critical process parameter” (CPP)— a process parameter whose variability affects critical quality indicators and which, therefore, is subject to monitoring or control to ensure the required quality as a result of the process;

“critical quality attribute” (CQA) — physical, chemical,biological ora microbiological property or characteristic that, to ensure the required quality of the product, must be within the appropriate limits and range or have an appropriate distribution;

"in-line" method— a measurement method in which the sample is analyzed directly in the process stream and is not taken from it;

“off-stream method” (on-line)— a measurement method in which a sample is taken from a process stream with possible return to the process stream;

“at-line method”— a measurement method in which a sample is taken from a process stream, isolated from it and analyzed in close proximity to the stream;

“continuous process verification”— an alternative approach to process validation in which the production process is continuously monitored and evaluated;

“design space”- a multidimensional combination and interaction of input variables (for example, material quality indicators) and process parameters that confirm the ability to ensure product quality. Work within the project scope is not considered a change. Exceeding the design scope is considered a change and usually requires approval of the changes after approval by the competent authority. The project field is proposed by the person who submits the applicationfor registration of a medicinal product, and is subject to assessment and approval by the authorized body;

"enhanced approach"— an approach to process development that uses scientific knowledge, research and risk assessment to identify and understand the characteristics of materials and process parameters that affect critical product quality indicators;

“control strategy” (control strategy) is a planned set of controls, developed based on existing understanding of the product and process, that ensures the suitability of the process and the quality of the product. Control elements may include parameters and characteristics related to active pharmaceutical substances and medicinal products, materials and components, operating conditions of premises and equipment, in-process controls, finished product specifications, methods and frequency of monitoring and control;

"traditional approach"— an approach to product development that establishes target values ​​and operating ranges for process parameters to ensure reproducibility;

“pharmaceutical quality system” (PQS)- a management system for directing and controlling a pharmaceutical company in relation to quality.

4. General provisions

1. Regardless of the approach used in drug development, traditional or advanced, before starting Before selling a medicinal product on the market, it is necessary to validate its production process. In exceptional cases (with a particularly favorable benefit-risk ratio for the patient), concomitant validation is allowed.
2. Process validation must confirm that the process, within the framework of the developed control strategy, is capable of ensuring product quality. Validation must cover all dosages intended for distribution and all production areas used to produce the marketable product. For different dosages, batch sizes and packaging capacities, extreme case studies may be acceptable, however, validation must be performed at all proposed production sites. Process validation data must demonstrate the suitability of the process for all products and at each production site. Validation must be carried out in accordance with the requirements of the Good Manufacturing Practice Rules, the obtained data must be stored at the place of production and be available for inspection, unless presentation in the registration dossier is required (in accordance with Section VIII of these Guidelines).
3. Regardless of the approach taken to develop a process, process validation can be performed in a traditional manner. Continuous process verification may be used if the process is developed using an advanced approach or if a significant amount of product and process knowledge has been gained from historical data and production experience. A combination of traditional validation and continuous process verification can be used. The use of on-stream, off-stream and off-stream monitoring techniques, often used in continuous process verification (as per Section V, Section 2 of this Guide), provides significantly greater information and knowledge about the process and can contribute to improvements. process.

5. Process validation

1. Traditional Process Validation

1. Traditional process validation is typically performed at the completion of pharmaceutical and/or process development, after scale-up of the manufacturing process, and before the finished product is marketed. As part of the product life cycle, some manufacturing process validation studies may be performed on pilot scale before scaling up the process. It should be noted that the size of the pilot industrial series must correspond to at least 10% of the size of the industrial scale series (that is, the scaling factor should be no more than 10). For solid oral dosage forms, the pilot batch size should generally be at least 10% of the maximum commercial batch size or 100,000 units, whichever is greater.

If the intended production batch size is less than 100 000 units, the predictive value of validation results obtained from pilot batches may be limited and the use of this approach must be justified. For other dosage forms, the size of the pilot batch should bejustified taking into account the risk to the patient caused by the inconsistency of quality for this dosage form.

1. Conducting full validation studies on pilot industrial batches is generally considered impractical, therefore, a process validation plan should be developed for each medicinal product (in accordance with the requirements in Appendix No. 1) for subsequent validation on industrial scale batches, and a study of extreme options. A process validation plan must be included in the registration dossier. The process validation plan includes a description of the manufacturing process, a list of tests to be performed and acceptance criteria, a description of additional controls in the process, and the data to be obtained. The rationale for the process validation plan should be presented in subsection 2.3 (General Quality Summary) of Module 2 of the registration dossier. Process validation information at the time of filing an application for registration of a medicinal product is provided for a commercial scale manufacturing process for non-standard products (for example, for biological (biotechnological) products) or if a non-standard method of production is proposed (in accordance with Section VIII of these Guidelines and according to Appendix No. 2).

In such cases, data for a number of consecutive batches of industrial scale must be submitted to the authorized body (expert organization) of the reference state, determined in accordance with the Registration and Examination Rules, within no more than 14 working days after receiving the conclusion on module 3 of the registration dossier. Number of episodes

must be justified based on process variability, process (product) complexity, process knowledge gained during development, supporting data obtained on an industrial scale during technology transfer, and the general experience of the manufacturer. Validation data from at least 3 industrial scale batches must be provided unless a different number of batches is justified. Data from one or two industrial-scale batches may be sufficient if pilot-scale batch data and appropriate justification are available (as outlined above).

1. Validation studies should include critical stages of the process, including additional testing (if necessary).

2. Continuous process verification

1. As an alternative to traditional process validation, continuous process verification can be used, in which the process is continuously monitored and evaluated. Continuous process verification can be used to complement or replace traditional process validation.

Continuous Process Verification is a scientific and risk-based approach to verify and confirm in real time that a process, implemented within specified parameters and approved documentation, consistently produces a product that meets all critical quality indicators and control strategy requirements.

1. The use of continuous process verification for the manufacturer (applicant) means conducting an extensive monitoring the process using in-line, off-line or in-line methods and monitoring product quality and process suitability for each batch. It is necessary to obtain appropriate data on the quality indicators of starting materials or components, intermediate products and the finished product. The data should also include verification and assessment of critical Quality Assurance (CQA) and Critical Process Parameters (CPP), including trend assessment. As tools for the practical implementation of continuous process verification can process analytical technologies (PAT) such as spectroscopy in the near-infrared region can be used spectrum (e.g. to determine mixing uniformity, granule surface area, homogeneity of content for large samples size) and multidimensional statistical process control(SPC).

1. The extent and extent of continuous process verification depends on a number of factors, including the following:

• a) prior knowledge of the development and production of similar products and (or) processes;
• 6) the degree of understanding of the process (details and detailed documentary characteristics) obtained during research during its development and as a result of experience in industrial-scale production;
• c) complexity of the product and (or) production process;
• d) level of automation of processes and used process analytical technologies (PAT);
• e) information based on product life cycle, process sustainability and manufacturing experience in industrial scalefor existing products (if necessary).

1. The justification for the suitability and feasibility of continuous process verification must be included in subsection 2.R.2. (“Pharmaceutical development”) of module 3 of the registration dossier and confirm it with data from laboratory or pilot-industrial batches. A description of the continuous process verification system, including the process parameters to be monitored and the material indicators used to control the analytical methods, must be included in the registration dossier with a cross-reference to section“Validation” (in accordance with Appendix No. 1 to this Guide). Evidence obtained through continuous verification of the industrial manufacturing process scale, should be available during an inspection of the production site. The applicant must identify and justify the selection of critical process steps and complete validation studies before marketing the product. Justification must be providedthe number of batches of product that will be used for process validation depending on the complexity and expected variability of the process and existing manufacturing experience. Continuous process verification is considered the most suitable method for validating continuous processes.

1. Continuous process verification can be introduced at any stage of the product life cycle. This approach can be used in the following cases: during initial commercial scale production, to test validated processes as part of a change management procedure and to support a continuous improvement process.
2. Continuous process verification is carried out in compliance with the principles and requirements of the Rules good manufacturing practices. Pharmaceutical quality systems (PQS) may complement the requirements of the Good Manufacturing Practices practices. However, questions related to the very procedure for compliance with Good Manufacturing Practice Rules and pharmaceutical quality systems should not be included in the registration dossier because data evaluation questions are carried out when inspecting the production of medicinal products for compliance with the requirements of the Good Manufacturing Practice Rules

1. practices.

1. Combined approach

It is possible to use a combined approach consisting of the traditional approach to validation and continuous process verification for various stages of production. The registration dossier must clearly define which validation approach is used at the various stages of the manufacturing process. The number of batches and batch size required for validation will depend on the extent to which continuous process verification is used. Unless continuous process verification is used for critical operations of non-routine processes (as defined in Section VIII of this Guide), they shall be subject to the process validation requirements in accordance with Section V, Subsection 1 of this Guide, unless otherwise justified.

4. Verification of the design field

When scaled up, an industrial process is typically implemented and validated within an appropriate area of ​​the design field, which is defined as the target interval or normal operating range. During the life cycle of a product, changes in process parameters and characteristics within the design envelope (that is, within the process operating ranges and material quality indicators) may result in the emergence of higher or undetected risks during design. For this reason, and depending on how the design field is initially defined and the process validated, it may be necessary to confirm the suitability of the new area within the design field (by providing evidence that all product quality indicators meet established criteria), i.e. verification of the design fields.

22. Unless the parameters studied during the development of the design field have been shown to scale independently of production scale, and the process has been validated using a traditional approach, verification of the design field and inclusion of a protocol for such verification in the registration dossier will be required. The use of continuous process verification can help validate the suitability of the design field throughout the product life cycle. In this case, design field verification should be considered as part of a continuous process verification system.

23. Depending on the variability of process parameters and characteristics and their movement across the design field (that is, fluctuations within the optimal operating parameters (validated ranges) or in a new area of ​​the design field with the emergence of more quality indicators (QA) and process parameters (PP's) not included in the routine process control system (for example, monitoring or testing by QA and PP's, which may depend on the scale of production and (if applicable) on the equipment. It is not necessary to verify all areas of the design field or the acceptable limits of the design field).

24. More than one area of ​​the design field should be verified, but a stepwise approach to adjusting the validated design field during the product life cycle is also acceptable.

6. Scaling

25. To avoid repetition of time-consuming and costly trials, it is necessary to properly collect information and research data during process development, optimization and scale-up. This information is presented to demonstrate that process scale-up can be achieved without loss of quality in an industrial production process. In subsection 2.Р.2 (“Pharmaceutical development”) of module 3 of the registration dossier, it is necessary to identify the process elements that will be critical during scaling; in subsection 3.2.Р.3 (“Drug production process”) of module 3 of the registration dossier, they must be characterized .

26. If batch sizes are offered in certain ranges, justification should be given that changing the batch size will not have a negative impact on critical process quality indicators (in accordance with Appendix No. 1 to these Guidelines), if the batch size is changed, they should be re-checked if evidence is not provided that the process is scale independent, or continuous process verification is not used.

7. Post-registration control of changes

27. Clear procedures should be established to manage changes proposed to the production process. Such procedures are part of the requirements of the Good Manufacturing Practices and are usually not specified in the registration dossier. Change control procedures should ensure that sufficient data is collected through the approved control strategy to confirm that the changed process produces the product of the required quality and ensure that all elements associated with the change are fully and thoroughly documented and approved, including an assessment of the need for change. in the registration dossier.

Detailed information about the changes that must be made to the registration dossier is given in Appendices No. 19 and 20 to the Registration and Examination Rules.

8. Standard and non-standard production processes

28. The provisions of this section apply only to processes that have been validated using a traditional approach, and not to processes where continuous process verification is used (in accordance with subsections 1 and 2 of Section V of these Guidelines). In accordance with subsection 1 of section V of these Guidelines, data when scaling up registration production dossiers for non-standard products or non-standard processes validated using a traditional approach must be provided. The applicant may provide justification that the product manufacturing process is standard for a specific production (production site), taking into account the risk to the patient due to inconsistency in the quality of the medicinal product or process. The assessment of such justifications is carried out on a case-by-case basis, but the information provided by the applicant (for each production site) must include:

• a) experience with the same or similar product or process (list of products registered (sold) in the territories of the Member States and the number of batches produced (including size));
• 6) name of products (number of registration certificates) in the relevant Member State;
• c) the amount of knowledge accumulated during product development (number and size of batches produced at each production site);
• d) historical data on the compliance of production sites with the requirements of Good Manufacturing Practice for this type of process.

29. In the application for registration, the applicant must indicate in subsection 2.Р.3.5 (“Validation of the production process and (or) its evaluation”) of module 3 of the registration dossier the category of the production process (standard or non-standard process) and justify the choice of the specified category.

Additional information considered as information on products (processes) is Appendix No. 2 to this Manual.

APPENDIX No. 1 to the Guidelines for process validation of the production of medicinal products for medical use

Requirements for a process validation plan

I. Traditional process validation

1. If traditional process validation is expected in accordance with subsection 1 of section V of the Guidelines for process validation of the production of medicinal products for medical use (hereinafter referred to as the Guidelines) if there is insufficient data obtained from industrial-scale batches, then the applicant submits to the authorized body of the government of a member of the Eurasian Economic Union in the field of circulation of medicines (hereinafter referred to as the authorized body) process validation plan. It specifies the scope and order of validation studies that will be carried out on industrial scale batches (the number of batches to be validated will depend on process variability, process and product complexity, and the experience of the manufacturer, But, usually consists of at least 3 consecutive series). Information on these studies must be available to authorized bodies for post-marketing inspection.

The process validation plan is included in the registration dossier provided for in Appendix No. 1 to the Rules for Registration and Examination of Medicines for Medical Use, approved by Decision of the Council of the Eurasian Economic Commission of November 3, 2016 No. 78, and contains, among other things:

• a) a brief description of the process indicating the critical production steps or critical process parameters to be monitored during validation;
• 6) specification for the release of the finished product (links to the relevant section of the registration dossier);
• c) detailed information about analytical methods (links to the relevant methods specified in the registration dossier);
• d) information about in-process control and acceptance criteria;
• e) information on proposed additional tests (with acceptance criteria and validation of analytical methods (if necessary));
• f) sampling plan (indicating the place, time and method of sampling);
• g) methods of recording and evaluating results;
• h) proposed research schedule.

1. The results of the validation are documented, signed by an authorized person and must be available for verification.

3. The report on the results of the validation must contain the following data:

• a) test results of product batches;
• 6) certificates of product analysis;
• c) protocols for the production of product batches;
• d) information about unexpected results obtained, deviations or changes made (with justification);
• e) conclusions.

1. If significant deviations from the expected results are received, the applicant immediately informs the authorized authorities about this, indicating corrective actions. All proposed changes to the manufacturing process must be approved by amending the registration dossier

II. Continuous process verification

1. If it is intended to use continuous process verification (in accordance with subsection 2 of Section V of the Guidelines), the applicant shall submit a plan for continuous process verification, including a description of the monitoring of industrial batches. The information provided must be available to authorized bodies for post-registration verification.
2. The continuous process verification plan is included in the registration dossier and contains (if necessary) the following information:

a) a detailed description of the use of monitoring to control process parameters using the “on-stream” (“on-stream” and “off-stream” method) (including the frequency of monitoring, the number of samples tested);

b) information about analytical methods and dimensions (links to the relevant methods specified in the registration dossier); c) eligibility criteria;

d) information, including, where appropriate, justification for the ability of continuous verification to support control of process reproducibility in the production of a product on an industrial scale, as well as information about the statistical methods of data processing used;

e) justification of how monitoring will contribute to the verification of the design field (during the development of the design field).

APPENDIX No. 2 to the Guidelines for process validation of the production of medicinal products for medical use

Guidelines for defining standard and non-standard processes

1. General provisions

1. The classification of a process as standard or non-standard is determined based on an assessment of the nature of the pharmaceutical substance, the nature of the finished product, the manufacturing process and the experience of the manufacturer.

All biological products are considered non-standard.

1. Products or processes that may be considered non-standard and for which industrial scale batch validation data are provided in the registration dossier (unless otherwise justified) include:

• a) production of specialized dosage forms;
• 6) inclusion of some new technologies into the normal process;
• c) specialized processes using new technologies or complex processes requiring special care;
• d) non-standard sterilization methods.

1. Technological operations in the production process of medicinal products that have not previously been used within the framework of the Eurasian Economic Union are, as a rule, considered non-standard.

2. Specialized dosage forms

1. Types of products that are considered specialty products include:

• a) drugs for metered dose administration into the lungs (for example, aerosol metered dose inhalers and dry powder inhalers);
• b) sterile suspensions, emulsions or other dispersed sterile liquids;
• c) drugs with modified release;
• d) single-dose drugs with a low content of active substance ( 2% of the composition);
• e) other specialized dosage forms (for example, parenteral depots based on biodegradable polymers, liposomes, micelles, nanoparticles).

3. Routine pharmaceutical processes incorporating new technologies

1. Properly designed and validated routine pharmaceutical processes may, for example, include a tableting step using wet granulation. However, the introduction of a new process step (e.g., a new drying technology) not typically used in the pharmaceutical industry into a routine process may require extensive validation based on data obtained during process and product development.

4. Specialized or complex processes

1. TO specialized or complex processes include:

• a) processes that include such critical stages as lyophilization, microencapsulation;
• 6) processes in which the physicochemical properties of the active pharmaceutical ingredient or key excipient (e.g. lubricants, coating agents) may lead to difficulties in processing or scale-up of production or problems associated with ensuring stability when carrying out the process on an industrial scale ;
• c) aseptic processes.

5. Non-standard methods of sterilization

7. K non-standard methods of sterilization include:

• a) terminal sterilization with moist heat using non-pharmacopoeial sterilization regimes;
• 6) final sterilization by ionizing radiation with an absorbed dose of less than 25 kGy.

Definition of Validation

By definition PIC/S
- these are actions that, in accordance with
with GMP principles prove that
a certain technique, process,
equipment, raw materials, activities or
the system really leads to
expected results

Purpose of Validation

Prove that the validation object
really leads to
expected results

The procedure for the validation process should
be recorded in a number of protocols and
validation results should be
recorded in records or reports.
These documents are used in different
forms upon receipt of registration
certifications and inspections in accordance with
GMP rules and also for internal
production goals to guide
the organization could be sure that
it controls its processes.

Validation Action Plan

is a document affecting
production activity in total
enterprises and specifying the timing of validation
and lists of equipment, systems, methods and
technological processes that are subject to
validation

The validation plan should include:

presented
format for drawing up a document according to
validation (in particular, the validation of equipment and systems from the point of view
in terms of installation qualifications, operational qualifications and
operational qualifications; on technology validation
process; on validation of analytical test results), and
The amount of information that should be reflected in the
every document.
the reasons and timing for revalidation are indicated
outlines the sequence of validation at each
production site
specific measures are stipulated in case of any deviations from
the listed tests and the terms after which,
another validation is allowed

Validation of analytical methods

Validation of an analytical method is
process by which, by
laboratory tests establish that
the characteristics of the technique correspond
requirements of the intended analytical
tests, where the main task is
experimental proof that
this technique is suitable for achieving those
the purposes for which it is intended.

Analytical Method Validation

Validation is documented
a procedure that provides a high degree of confidence
is that a particular process, method or system
will consistently lead to results,
meeting pre-established criteria
acceptability.
In accordance with international requirements for
validation of analytical methods any
being developed or modified
the analytical technique must be evaluated from the point of view
in terms of its validity and objectivity
use.

Purpose of Analytical Validation

- guarantee that the selected analytical method
will provide reproducible and reliable
results consistent with the set goal.
It is necessary to properly determine
both the conditions for applying the methodology and the goal for
which it is intended for.

Analytical methods used for:

1. Identification of the medicinal substance.
2. Setting limits for impurity content
related
connections,
heavy
metals,
residual
organic solvents.
3. Quantitative determination of medicinal
substances, medicinal substance(s) in
composition of dosage forms, individual
impurities
And
amounts
impurities
products,
preservatives.

Analytical Method Validation Parameters

Right
Precision
Specificity
Detection limit or sensitivity
Limit of quantitation
Linearity
Analytical domain (range)
Stability (robustness)

Accuracy, trueness

analytical method characterizes the closeness of the results
tests obtained by this method to the true
meaning.
An indicator of the correctness of a method is usually the value
systematic error.
Systematic error is expressed as the difference between
mathematical expectation of measurement results and true
meaning.
Correctness is assessed based on at least 9 results
determinations at a minimum of 3 concentration levels within the limit
analytical area (for example, 3 repetitions of determination
for 3 analytical concentrations).

Precision

analytical technique expresses closeness
results (degree of scatter) of series of measurements,
obtained from multiple samples of one sample
under given conditions.
Typically, 3 levels of precision are examined:
- repeatability
- intermediate precision
- reproducibility

Repeatability is a measure of precision at the same
operating conditions for a short period
time, that is, under normal operating conditions
analytical methods on the same equipment.
This indicator is sometimes called intra-experimental
precision (repeatability precision).
The ICH recommends that repeatability should be assessed
using the results of at least nine determinations,
covering a specified range of techniques (e.g.
three concentrations/three replicates, as in the test for
correctness), or at least six definitions with
100% concentration of the test solution.
Requires representation of the calculated standard
deviation, relative standard deviation

Intermediate precision – variability within
one laboratory.
The standard parameters determined in this case
are variations across days, analysts, and equipment.
ICH
allows
Not
determine
intermediate
precision,
If
proven
reproducibility.
Intermediate precision is expected to be
show variability of the same order of magnitude or less than
variability in reproducibility.
ICH recommends that standard values ​​be included in the report.
deviations,
relative
standard
deviations
(coefficient of variation) and confidence interval.

Reproducibility – measures interlaboratory
precision.
This parameter is considered during standardization
analytical technique (for example, when turning on
methods in the pharmacopoeia and transfer of methods between
different laboratories).
To validate this characteristic, it is necessary to carry out
identical studies in different laboratories using
identical homogeneous test samples and identical
experimental plan.

ability to reliably determine medicinal
substance in the presence of impurity compounds,
degradation products and excipients
Specificity is assessed during validation
methods used for:
- identification of medicinal substances,
- determination of impurities (related compounds,
heavy metals, volatile organic impurities),
- establishing the quantitative content of a substance in
sample and dosage form.

Specificity of the analytical method

In authenticity tests, the analytical method must
ensure the identification of a medicinal substance in the presence
other compounds of similar chemical structure. It should be
supported by obtaining positive results (by comparison with
standard) for analyzing a sample containing a medicinal substance, and
also negative results of analysis of a sample that does not contain
such substance, to confirm that a positive result is not
may be due to the presence of others similar in structure to it
substances.
In cases where impurity compounds and degradation products are not
identified or their reference materials are missing,
the specificity of the analytical method must be justified
results of determinations by another, independently validated method.
In this case, the analyzed samples should be subjected to stress
influences (light, temperature, humidity, acid/alkaline
hydrolysis, oxidation).

Specificity of the analytical method

At
quantitative
definition
impurities
the specificity of the method can be proven by adding to
medicinal substance in appropriate quantities
impurities or excipients for evidence
that the presence of these substances does not affect the result
analysis.

Detection limit (DL)

the minimum amount of analyte in a sample that can be
be discovered, but not necessarily identified in
quantitative
respect
at
given
conditions
experiment.
The detection limit is expressed as the analyte concentration
in the sample, such as percentage, parts per million (ppm) or
parts per billion (ppb).

Detection limit (DL)

There are several approaches to defining software:
- when validating instrumental techniques, the presence of background noise is usually
compare measured signals from samples with known low concentrations
analyte with control (blank) samples.
The minimum concentration at which the analyte can be reliably determined is
established by using an acceptable signal-to-noise ratio of 2:1 or
3:1. The presentation of the corresponding chromatograms is sufficient to justify
software values.
- another approach is to calculate the software based on the standard deviation
response and slope of the calibration curve. The standard deviation is determined either
based on standard deviation of multiple determination results
control (blank) samples, or based on the standard deviation of values
segments cut off by regression curves on the axis in the range of the expected software.
Such an assessment requires subsequent validation by conducting separate
determining the appropriate number of samples containing the analyte in amounts close to or
equal software:
PO = 3st/S, where
st – standard deviation of the response; S – slope of the calibration curve.

Limit of quantitation (LOQ)

the minimum concentration at which an analyte can be
reliably quantified at the ratio
signal/noise ratio 10:1.
In the second approach, the LOC is determined by the formula:
PKO = 10st/S
The LOQ of the technique is affected by the sensitivity of the detector and
accuracy of sample preparation at low concentrations of impurities.
In practice, the LOQ should be lower than that recommended by the ICH
limit of impurity content, the presence of which is necessary
indicate in the registration dossier.

Linearity of the analytical procedure

is the ability (within a given range)
receive test results in the form of variables
(for example, absorption values ​​and area under
curve), directly proportional to the concentration
(amount of analyte) sample.
Variables that can be used for
quantitative
definitions
analyzed
substances are peak areas, peak heights and
ratio of the areas (heights) of the peaks of the analyzed
substances to the peak of the internal standard.

There are two approaches to determine linearity
techniques:
- during the first one, various samples are taken directly
standard sample for preparing solutions of different
concentrations to determine linearity. This method
not suitable for preparing solutions with very low
concentration due to a fairly large error at
weighing;
- in the second approach, a high-quality initial solution is prepared
concentration. Linearity is determined in solutions
obtained by direct dilution of the original standard
solution. This method is the most common and often
recommended.

Determination results should be used
at least five concentrations.
At
normal
conditions
linearity
counts
acceptable
at
coefficient
determination
(square
coefficient
correlations) > 0.997.
In accordance with ICH requirements also
the slope of the curve must be calculated,
the residual sum of squares and the size of the segment,
cut off by the curve along the y axis.

Analytical Method Range

interval between maximum and minimum
concentration of the analyte in the sample, for
whom
was
shown
acceptable
level
precision,
correctness
And
linearity
analytical technique. The range is usually expressed in
the same units (for example, percentages, parts on
million) are the same as the test results obtained with
using analytical techniques.
For
techniques
quantitative
definitions
pharmaceutical
substances
or
ready
medication is usually recommended to
the range was 80-120% of the nominal concentration.

ability
techniques
stay
unchanged
at
small,
But
deliberate variations in parameters
techniques;
she
is
information
O
reliability under normal use.

Robustness (stability) of the analytical technique

Variability parameters:
1. Sample preparation:
- extraction time;
- solvent for preparing the test solution (pH ± 0.05 units, %
organic solvent content ±2% (amount of pure solvent);
- membrane filters;
- stability of the test and standard samples.
2. High performance liquid chromatography (HPLC) conditions:
- composition of the mobile phase (pH ± 0.05 units, % organic content
solvent ±2% (amount of pure solvent);
- column used (equivalent columns, series and/or suppliers, age
columns);
- temperature;
- flow speed.
3. Gas chromatography (GC) conditions:
- column used (series and/or suppliers, age);
- temperature;
- flow speed.

Classification of methods used for pharmaceutical products

Analytical methods used for quality control
Medicines are generally divided into 4 classes:
- class A – tests designed to establish authenticity
both the medicinal substance and individual ingredients in the finished
medicine;
- class B – methods designed to detect and
quantification of impurities as in medicinal
substance, and in finished
dosage form;
- class C – methods used for quantitative determination
medicinal substance or main ingredient in the finished product
medicine;
- class D – methods used to evaluate the characteristics of finished products
drugs, such as “solubility indicators” and
"uniformity of dosage".

The table shows the characteristics that are taken into account for
various classes of techniques, i.e. degree of significance of validation parameters
Table 1 - Characteristics used in determining various indicators
quality of medicines
Name
characteristics
Authenticity
Right
Accuracy
Reliability
Linearity and
Range
Selectivity
Limit
Detections
Limit
quantitative
definitions
Quality indicators
Definition Quantitative Characteristic
impurities
definition
FPP
(dissolution,
uniformity,
dosage)
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
+
Trial
to the limits
+
+
+
+
+
-

For example, when determining authenticity, it is important
ability of the technique to determine the minimum amount
substances and not respond to changing conditions and to
the presence of other components in the preparation, i.e. special
what matters is the detection limit, reliability and
selectivity.
When quantifying a drug
substances, the closeness of the results to the true value is important,
the degree of scattering of results, the ability not to respond to
change
conditions,
give
results,
directly
proportional
quantity
substances
V
sample
the ability to determine minimal amounts of a substance,
those. correctness, accuracy, reliability, linearity and
detection limit.

These general rules may have
exceptions,
When
characteristics,
marked in the table as not required may
be necessary, and vice versa.
In addition, the choice of characteristics and
the depth of their study is influenced by the purpose,
for which the method is claimed.

Types of Validation

Validation is divided into the following types:
- promising;
- accompanying;
- retrospective;
- revalidation.

Prospective Validation

carried out by the central laboratory and quality control department at the project preparation stage
FSP for new drugs or when revising the FSP, if
are introduced
new
analytical
techniques.
AM,
developed by TsZL for FSP projects on drugs,
initially validated in the Central Laboratory. Then they
undergo validation studies in QC for
confirmation and comparison of validation results.
When validating each AM in QC it is necessary
repeat the main part of the validation studies,
using accuracy experiments and
right.

Related Validation

carried out in the Central Laboratory and OKK at the preparation stage
FSP project to replace the existing FS (VFS), if
previous validation studies for AM,
included in the FS (VFS), were not carried out.
All methods when conducting validation
studies must demonstrate a lack
influence of other components of the test sample on
results of determination of the analyte.

Retrospective Validation

carried out in the OKC using the method
quality control cards. This type of validation
AM is used provided that the composition of the drug,
maintaining the technological process and methodology
quality control will remain unchanged.

carried out in a number of cases when there are
changes in the synthesis of the drug, in the composition
of the finished drug and changes in the methodology itself. Revalidation
is divided into two categories:
- revalidation after a known change that
may affect product quality (including transfer
process from one enterprise to another or from one
plot to another);
- periodic revalidation carried out according to schedule
through certain
periods of time.

Revalidation of AM (re-validation)

Revalidation is carried out in case of the following changes:
a) suppliers of raw materials (change in the physical properties of the original
raw materials, such as density, viscosity, particle size, etc., can affect
mechanical properties of raw materials and, as a result, adversely affect
process or target product);
b) primary packaging materials (for example, the use of polymer
materials instead of glass may require process changes
packaging, using other equipment, conducting research
stability, etc.);
c) regulatory requirements for the quality of the finished product;
d) volume of the series;
e) composition of the finished product;
f) process evaluation criteria;
g) during the technological process;
h) equipment (replacement of equipment and its repair; redevelopment and/or
repair of production premises and engineering systems).

Revalidation of AM (re-validation)

Revalidation should also be carried out:
- in case of deviations identified during serial production
products;
- when transferring the process to another production or to another
plot;
- in case of unexpected changes that may occur
identified during
carrying out self-inspection.
Validation results are documented in a protocol
validation.
The validation protocol is drawn up separately for each type
analytical technique.

Validation of production systems and equipment

Recently it has become standard practice
inclusion of the “qualification” procedure within
"Validation". PIC/S defines "qualification" as
identification of equipment properties associated with
performing special functions, and defining
specific limits or data limitations
properties.

Requirements for systems and equipment

- systems and equipment are suitable for the intended purpose
use
V
compliance
With
developed
documentation;
- systems and equipment are correctly installed, in
in accordance with the development documentation;
- systems and equipment are equipped with suitable
instructions and procedures (for example, for maintenance and
repair, calibration, cleaning) necessary for
performance of work;
- systems and equipment operate under normal
conditions and under “worst case scenarios” within the limits
specified in the development documentation.

Qualification of critical equipment and systems must be completed before process validation work can begin. Qualification usually

carried out in the following steps:
Design Qualification DQ – refers to the period before installation
equipment. It defines operating
and functional specifications/requirements
to equipment and details of justified
decisions in choosing a supplier.

Design Qualification (DQ)

The stage includes:
- supplier selection is based on the following
criteria: presence in the production nomenclature or
supply of devices of the required type, technical
level of products and reputation of the supplier in the market,
presence of a representative in Russia and procedure
support of the device in operation.
- choosing the right device
- selection of additional accessories (options).
All this is done before making a purchase decision.

Installation Qualification (Installation Qualification – IQ)

relates to the installation of equipment and determines that the resulting
the equipment meets its purpose and requirements,
that it is properly installed in the selected configuration, and
which is suitable for the relevant job. Carried out in the following cases:
purchasing a new or used device,
moving the device from one place to another within the enterprise.
Performed when the device is delivered to the place of operation. Wherein:
- compliance of the supplied equipment with the order is checked and
completeness of delivery, including documentation;
- a place is being prepared for installation of equipment (that the equipment
can be placed in a place allocated for it, must be
checked when ordering);
- the supply of necessary communications (electricity,
water, compressed air, etc.).

Operational Qualification (Operational Qualification – OQ)

process,
showing
What
equipment
will
function according to work/operational requirements for
him in the selected configuration. Validation of OQ is carried out when
subject to successful completion of IQ equipment validation. She
may be fully or partially combined with IQ based on
specific situation. The list of works may include: unpacking,
assembly and installation of equipment intended for it
place in accordance with the manufacturer's requirements (done
representative
manufacturer,
specialized
organization or user if necessary
preparation); checking fixed (unchangeable) parameters
device, software and functional tests
(carried out according to the manufacturer's instructions).

Operational Qualification (Performance Qualification – PQ)

process showing that the equipment
is constantly operated in accordance with
specification - conditions suitable for its
routine use. PQ validation is carried out
subject to successful completion of IQ and OQ. She
designed to confirm correct operation
device under operating conditions. Scope of work
may include performance tests
using control tests, OQ tests,
but in an extended range, etc.

IN
further,
at
operation,
examination
performance
performed
By
instructions
manufacturer at certain intervals. Possible
different options, for example, checking before each
use if necessary. User
must
lead
archive
data
O
checks
performance of the device and its operation, which may
serve as a basis for confirming the correctness
determining the frequency of inspections.
After fully qualifying the equipment, we can
move on to the validation of analytical methods.

1. The pharmaceutical enterprise must have
an employee responsible for conducting validation has been identified,
who forms the working group and appoints it
leader. The head of the working group draws up a plan
conducting validation with maximum consideration of accumulated
earlier information.
The plan must be agreed upon by all interested
departments (design, engineering, research, production, control
quality) and approved by the employee responsible for
conducting validation.
2. Working group and representatives of interested parties
departments performing validation work are responsible
responsibility for its implementation in accordance with the plan.

Processing and registration of validation results

3. Personnel involved in the work of carrying out
validation, must undergo appropriate training
(instruction).
4. The validation report must contain:
-target;
- background information;
- information about the calibration of measuring instruments;
- protocols of the results obtained for compliance testing
installation, equipment performance and conditions and
process parameters specifications and
regulatory documentation;
- analysis of the results obtained, proposals and conclusions;
- requirements for re-inspection.

Processing and registration of validation results

Based on the results obtained
the head of the working group draws up a report on
conducting validation.
The employee responsible for conducting
validation, approves the report and issues
conclusion
O
compliance
object
(equipment, technological process, etc.)
requirements
normative
and/or
technological documentation.

Sample Contents of a Validation Report (Recommended)

1. Validation object and its identification, date (period) and location.
2. Purpose and type of validation.
3. Identification of validators (full name, position, signature, date);
4. Background information:
4.1. General characteristics of the object, including critical parameters.
4.2. List of documentation (regulations, pharmaceutical articles, design documentation, instructions,
specifications, certificates, passports, etc.).
4.3. List of test methods (measurements, sampling, etc.) and evaluation criteria
results.
4.4. Information about involved organizations or experts.
5. Information about calibration/verification:
5.1. Measuring instruments (instruments, sensors, scales, etc.) installed in equipment, engineering
systems, premises, etc.
5.2. Measuring instruments used during validation/qualification.
6. Documents:
6.1. Validation protocols of all stages of qualification (DQ, IQ, OQ, PQ) and process validation (PV),
or a link to them indicating the storage location.
6.2. Protocols (reports, etc.) with data and results of tests, sampling, etc.
7. Analysis of the results obtained, incl. By:
7.1. Checking critical conditions and parameters.
7.2. Identified deviations (changes) requiring corrective action.
7.3. Occupational health and safety conditions.
8. Conclusion based on the validation results.
9. Timing for repeated planned validation.