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Quality of medicinal products: relationship between normative document and specification, application dossier, pharmacopoeia, and GMP
Quality of medicinal products: relationship between normative document and specification, application dossier, pharmacopoeia, and GMP
Normative documentation, specification, quality, quality control strategy, pharmacopoeia, manufacturing, GMP
For a long time, normative documentation (also known as ND) has been the main medicinal product quality control tool in Russia. Such an unbalanced use of one instrument at the expense of other methods of quality assurance has resulted in disproportion towards a single document which ceased functioning adequately. To understand the current situation and find the approaches to overcome this problem, it is worth examining the history of the document and analyzing how an ND correlates with specifications, marketing authorization application dossiers and pharmacopeias, and reflect how an ND is used in the course of assessment of a marketing authorization application dossier or GMP inspection. All these should be taken into account by the foreign companies which want to penetrate the Russian pharmaceutical market.
By 2016, a disproportional regulatory situation was established in Russia; a normative document, i.e. a single document intended for quality control of a finished medicinal product, had become equal to the whole part of marketing authorization application (MAA) dossier dedicated to quality control of a medicinal product and active substance. However, the normative document (ND) only partly corresponds to the globally-accepted concept of specification (the ND is not equal to the spec). Thus, an element of a quality control strategy has replaced the entire quality assurance system, i.e. reductio ad simplex has occurred.
A finished product specification drawn up by the manufacturer and approved by the competent authority is a globally recognized element of the quality control strategy; unlike an ND in Russia, it is not that important as a quality control tool within the pharmaceutical quality system. The significance of an ND for quality control is overly exaggerated. However, for a long time, an ND used to be almost the sole instrument of the quality control strategy to the prejudice of other tools, such as Good Manufacturing Practice (GMP), process validation, characterization, stability testing, etc.
The document has become so important in Russian pharmaceutical environment that ‘professionals’ have emerged who prepared an ND. However, in contrast to medical writing (i.e. writing of medical texts such as a clinical trial protocol, investigator’s brochure, clinical study report, Summary of Product Characteristics, etc.), it is not possible to create an ND without detailed knowledge of the manufacturing process, overall quality control strategy, non-clinical and clinical data, stability data, capabilities and limitations of analytical methods, validation data, or, after all, a Target Quality Product Profile (QTTP) of a specific finished product. Putting it otherwise, an ND, being a sort of specification, should be based on the experimental data and risk analysis related to clinical context, attributes of the finished product and its starting materials and manufacturing process characteristics.
It is important to emphasize that it is unacceptable to reduce such a global concept as quality is to a mere ND. Hence, it is worth addressing these concepts more thoroughly. All these should be taken into account by the foreign companies which want to penetrate the Russian pharmaceutical market.
Quality and normative document
Russian legislation defines quality and a normative document via each other. The following definition of quality is given in the pharmaceutical legislation :
The quality of medicinal products means compliance of a medicinal product with the requirements of a pharmacopoeial monograph or, where the latter does not exist, of a normative documentation or normative document*.
At the same time, a normative document has the following meaning”:
a document which contains a list of medicinal product’s quality attributes, quality control methods, established by the manufacturer and to be evaluated during the assessment.
The comparison of two definitions (and taking that a normative document equals to a pharmacopoeial monograph; see below) indicates that the definitions of quality and a normative document refer to each other so that the meaning of both terms remains quite vague.
At the same time, there are generally accepted definitions of quality. One can find a general definition given by the International Standardization Organization (ISO) and a specific definition used exclusively in respect of a medicinal product. The specific definition is given in the ICH guidelines, specifically in ICH Q6A and Q6B dedicated to preparing specs. The definition given in the ICH guidelines is used in the EAEU documents .
According to ISO, quality means the totality of features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs . The definition is general and suits any situation, such as food, cosmetics, manufacturing processes, or management systems. The significant elements of the definition will be discussed next in more detail.
First of all, it is stated that some needs do exist which relate to features and characteristics of a product or service. These requirements are implied externally (i.e. they exist outside the quality system), and the product or service is created to meet those needs. Thus, the needs are the subjective side of quality because they are rendered by a human being to meet his/her subjective demands. Then, the product or service together with the totality of its inherent features and characteristics should be considered. Usually, these product or service characteristics are material and measurable, i.e. exist objectively. Thus, using simplification, one can say that quality is a measure to what extent objectively existing material parameters satisfy subjective demands or that a product has good quality when it complies with the requirements specified by the client. It is important to understand that the needs cannot be derived from the product itself because they exist outside the quality system.
It is worth addressing the specific definition of pharmaceutical quality. From the regulatory point of view, quality means the suitability of either a drug substance or drug product for its intended use. . This term includes such important attributes as the identity, strength, and purity.
This definition is a specific definition derived from the general definition in respect of a medicinal/drug product. Let’s analyze it more thoroughly.
The subjective aspect of the quality of a medicinal product is its intended use. The intended use means the totality of the target population (e.g., adults, children), an indication (e.g., local treatment of glaucoma), route of administration, duration of treatment, comorbidities, concurrent medication, and other characteristics of human needs from the perspective of his/her health. The objective side of the quality is an active substance/active pharmaceutical ingredient (API) and finished drug product together with all their inherent features and characteristics. Among them, ICH delineates the main attributes: identity, strength, and purity. These three attributes of an API and finished product are the most critical to determining their suitability for the intended use [critical quality attributes].
Thus, the quality of a medicinal product (including the quality if its starting materials) is a broad concept which is not confined by the simple compliance of some attributes to certain criteria determined by its manufacturer regardless of implied needs of the target population. However, this narrow understanding prevails in Russia today. Therefore, to fully understand this broad concept, it is reasonable to refer to the concepts of the pharmaceutical quality system and product lifecycle from the quality point of view. These issues are discussed more thoroughly elsewhere [5,6].
As mentioned above, an ND contains several sections, including the spec. The definition of a specification is given in ISO and ICH documents. The ICH definition is used in EAEU pharmaceutical legislation.
According to ISO, specification means a document that provides requirements . According to ICH, specification means a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use .
It is obvious that the core difference between domestic and accepted definitions consists in that the medicinal product quality is not a mere conformance of a product with its ND but rather meeting of requirements implied by a client depending on the intended use of that medicinal product.
It is worth considering the history of an ND to understand how this document became crucial for quality assurance of medicinal product in Russia to the prejudice of other tools of quality assurance and quality control.
History of a normative document
The term ‘normative document’ was used for the first time in the ‘Instruction on the rules of assessment, clinical trials, and approval of foreign medicinal products and substances’  and ‘Instruction on the rules of assessment, approbation, and approval of medicinal products manufactured in CIS or Baltic countries in Russia’ . Both documents were approved by the Ministry of Health and Medical Industry of Russian Federation in 1996; however, they were repealed several years ago.
According to these instructions, an ND was a quality control instrument for a medicinal product imported in Russia; the ND would not be issued to the manufacturer of the authorized medicinal product. Thus, an ND was drawn up by the regulatory authority only for the purposes of quality control of foreign medicinal products.
The Pharmacopoeial Committee used to send an ND to institutions where it was used: State Scientific Research Institute for Standardization and Control of Medicinal Products [which subsequently has been converted to the current Medicinal Products Assessment Institution under Ministry of Health] and other institutions for quality control of medicinal products and substances. Following the MAA process, an applicant would receive the Certificate of a Marketing Authorization together with the medication guide approved by the Pharmacology Committee. Thus, a foreign manufacturer would perform quality control procedures using their quality control strategy, including in-house specifications which were not even considered by the Pharmacopoeial Committee.
At the same time, the term a ‘normative document’ was not included in the Federal law of 22 June 1998 #86 ‘on medicinal products’  (from now on referred to as FL-86). The law would lay down requirements for quality of medicinal products and define the quality as conformance of a medicinal product to the State quality standard of a medicinal product. The term ‘ND’ was not defined in the law and was not used thereof.
To establish the aforementioned quality standards and pursuant to FL-86, Industry Standard (OST 91500.05.001-00)  has been established. The OST did not stipulate drafting an ND, and it did not cover medicinal products manufactured abroad. Therefore, the Standard used to cover domestic medicinal products and prescribe development and approval of a so-called site pharmacopoeial monograph (SPM) by the manufacturer. Since then, an unspoken rule was established envisaging development and approval of an ND for foreign medicinal products and an SPM for domestic medicinal products.
It should be emphasized that neither Instructions nor Industry Standard mentioned the rationale and grounds for developing an ND or SPM as well as pharmacopoeial texts. Being a sort of specification, these documents should be developed directly (by the manufacturer) or indirectly (using pharmacopoeial texts) based on the non-clinical/clinical study results, API, finished product, and process characterization data, process validation studies, and stability data. However, this has never been formally specified, so up until now the creating and assessment of an ND (or SPM) is being done without correlating the information contained thereof with the aforementioned data.
The term ‘normative document’ re-emerged in the Federal law of 12 April 2010 #61-FZ ‘on medicinal products circulation’  (FL-61) which is effective to date. An SPM is not mentioned in FL-61, and Industry Standard was canceled in 2015. However, for domestic medicinal products, an SPM is still approved, and an ND is approved for foreign medicinal products. The official rules describing the procedure for developing those documents have not been made yet.
In contrast to an FSM, an ND would be prepared only for quality control purposes by Russian official laboratories but not the manufacturer itself for release testing because foreign manufacturers have always been using a specification. An ND has been prepared exactly for the purposes of the official quality control within Russian Federation since official laboratories could not perform each analytical test envisaged by any given specification. At this time, the assessment authority has started to ‘improve’ analytical tests and an ND in general in view of official quality control. Such an improvement was based only on capabilities of the official quality control laboratories and later on capabilities of the laboratory of the assessment authority only, within marketing authorization or variation procedures.
Additional confusion arose when new amendments to FL-61 became effective in 2016 which introduced Common Technical Document (CTD) format of MAA. Since then, an ND is designated as an administrative document, and in the quality module of a MAA dossier, such terms as a drug substance specification and finished product specification are used. We assume that being an administrative document and having a separate specification, an ND is not intended to be used by the manufacturer for release testing purposes. However, an ND is mentioned in Articles 47 and 49 of FL-61 among documents used to demonstrate the quality of imported medicinal products. No clarification is given so far on how an ND and spec correlate to each other.
Taking into account aforementioned inconsistencies, it is worth comparing an ND and spec together with other documents and standards. Now on the term ‘ND’ will be used to mean both an ND and SPM.
ND vs. spec
According to the repealed Industry Standard, an ND for a finished product shall contain the following sections: the title page, a spec itself, a description of a finished product composition, a brief description of an active substance, a description of test methods, and a description of container(s) and package labelling.
An ND begins with the title page which contains information on the finished product manufacturer, namely its name and country of establishment. Where several manufacturers are engaged, information on all them should be provided. The exact address including the geographical position (e.g. using GPS) need not be included. Thus, this section is used for introductory purposes only and is not intended for quality control. However, if a MAA dossier is in CTD format, this information is provided in sections 3.2.S.2.1 (DS) and 3.2.P.3.1 (DP) in detail. There is an explicit requirement for completing these sections, in particular, it is insufficient just to mention the manufacturer’s name and country of establishment. Hence, the title page shall be considered a redundant section.
The specification itself is similar to the generally accepted concept of specification. However, it additionally contains package labeling. The main drawback of an ND specification is that the acceptance criteria included therein are not justified. They are either derived from foreign pharmacopeias or improvised; the choice of test methods is also not justified by any scientific data. In other words, there are no requirements to justify information to be included in an ND on sound scientific grounds. Particular problems arise when developing an ND for a finished product of a non-compendial substance. The latter is the case, for example, for most of the new medicinal products. CTD format envisages dedicated sections which contain justification of specifications: 3.2.S.4.5 (DS), 3.2.P.4.4 (excipients), and 3.2.P.5.6 (DP). The lack of such information in an ND may explain arbitrary requirements by assessors to ‘improve’ the ND without any correlation with the quality control strategy.
Then a description of a finished product composition is given; no requirements on how to complete this section exist as well. CTD section 3.2.P.1 includes detailed standardized criteria not only for the description of a finished product composition but also for other components of a drug product, including its container, solvents, delivery devices, etc.
After the description of a composition, a brief description of a drug substance is to be provided. Similar information is included in Section 3.2.S.1.2. The difference consists in that this information does not correlate with other information included in an ND, and in a CTD format MAA dossier the description of an active substance is an integral part of pharmaceutical particulars provided to the regulatory authorities, and it closely relates to other CMC sections including 3.2.S.3 Characterization. The latter is not envisaged in an ND.
One of the most important section for assessors is a description of test methods; it is subject to special scrutiny and regularly ‘improved’ following requests of the assessment body. In CTD format dossier, this information is provided in 3.2.S.4.2, 3.2.P.4.2, and 3.2.P.5.2 for active substance, excipients, and finished product, respectively. It is worth noting that during assessment in Russia, only a finished product ND is examined and in other countries, any in-process or end-product materials, such as starting and raw materials, intermediate products, or excipients are subject to assessment.
It is also worth separately mentioning that an ND (and a pre-2016 Russian MAA dossier in general) does not contain any analytical procedure validation information, and an obligation to include validated analytical procedures into an ND does not exist. At the same time, a CTD dossier has three sections devoted to analytical procedure validation data: 3.2.S.4.3, 3.2.P.4.3, and 3.2.P.5.3. Moreover, when choosing ND specification acceptance criteria, test method capabilities are not taken into account, in particular, analytical precision which reflects method variability.
Next, an ND includes a description of a container and package labeling. Providing this information within the ND does not also achieve any of the purposes of the document. In particular, labeling is an element of product information which is closely related to Summary of Product Characteristics/Patient Leaflet. Moreover, the labeling information should be publicly available and not included in a document which contains commercial or industrial secrets. Being part of the product information, labeling should be assessed from the perspectives of patients and healthcare professionals and not buried in pharmaceutical documentation accessible only by quality assessors. Container data is included in an ND only for ‘informational’ purposes, and it does not facilitate quality control activities since the extensive description of all packaging materials, their composition, test methods, etc., e.g., extractable and leachable profile, is not provided in an ND. This information is to be included in sections 3.2.S.6 and 3.2.P.7 in CTD format.
Taking into account aforementioned, improvement of analytical test methods and an ND specification itself based on capabilities of an official control laboratory contradicts to the aim of release testing and, in general, quality control strategy established by the manufacturer based on test/study and other experimental data. Inclusion of scattered information on other manufacturing and quality control aspects into an ND also does not add any value because it yields an inconsistent compilation of information which is declared without any support by experimental and/or literature data. This fact is the main reason that an ND does not have a strong correlation with actual manufacturing and quality control activities performed within manufacturer’s pharmaceutical quality system. It is not possible to produce good quality medicinal products using only an ND because of both the flawed development methodology (or absence thereof whatsoever) of an ND and insufficient quality control tools provided thereof.
Where the information contained in an ND needs to be amended, the justification of such a variation almost exclusively rests on manufacturing process grounds without any analysis of the impact of such changes on the safety and efficacy profile. It means that these variations are not meant to ensure suitability of a medicinal product to its intended use, i.e. its quality.
It should be pointed out that since the Industry Standard of 2001 and Instructions of 1996 had been repealed, formal requirements to develop an ND or SPM have been adopted. However, elaboration of a specification (and consequently appropriate parts of an ND) should at least partly be guided by the pharmacopeia. Hence, it is worth discussing how an ND (and CTD format specifications) correlate with compendial requirements.
Normative document vs. Pharmacopoeia
Pharmacopoeia is a compendium of minimal standards for quality control of different articles used in the manufacturing of pharmaceuticals [11,12]. Such materials include drug substances, excipients, finished drug products, container closure materials, starting/raw materials, intermediate products, etc. Moreover, some pharmacopeias, such as the USP, regulate different quality aspects of articles used in food, cosmetic, and other industries making products for consumers, including medical devices and food supplements .
It is important to stress that pharmacopeia provides minimal quality standards . However, among Russian pharmaceutical industry professional, an erroneous perception prevails that pharmacopoeial standards cover all quality aspects, and that pharmacopeia provides optimal indisputable test methods and acceptance criteria for any given substance or product. To show that such a perception is misleading, it is useful to briefly describe how pharmacopoeial monographs on different articles get prepared in the United States.
To include a new drug substance into the USP, the manufacturer of the drug substance and drug product should submit manufacturing and quality control data of those articles, including specifications, full description of test methods together with validation data, detail description of manufacturing method (route of synthesis), full characterization data on the drug substance (among others, its origin, isomery, crystalline forms, hydrates and solvates, etc.) as well as reference standards, to the USP Convention .
After the USP Convention receives this data and materials, it starts a thorough analysis and improvement and interlaboratory validation of analytical methods. The acceptance criteria remain the same (at least they do not get relaxed) because they are based on non-clinical and clinical data .
Similar approaches are used in the European Union and Japan, including the obligatory interlaboratory validation [16,17]. These pharmacopeias collaborate with each other to harmonize existing standards. In our country, we regularly adopt and adapt texts of foreign pharmacopeias regardless of the data contained in the MAA dossier of the drug product whose ingredients (the drug substance, excipients, or packaging materials) need preparing a monograph and without any interlaboratory validation.
These imply the following practical conclusions. A pharmacopeia contains minimal quality standards for active substances, finished products, excipients, container closure materials, raw/starting materials, and intermediate products. Complying with these standards is sufficient for medicinal use of those articles; however, pharmacopoeial standards cannot ensure consistent and robust manufacturing process and quality control as well as the safety and efficacy level which is higher than a minimal pharmacopoeial standard.
This is why specifications of high-quality medicinal products usually contain more tests and stricter acceptance criteria as well as more efficient test methods than prescribed by the pharmacopeia. Therefore, assessors should not generally request manufacturers to reduce the specification (turning it into an ND) in order make it compliant with the pharmacopeia.
Pharmacopoeial monographs are drawn up based on specifications of innovator drug products and components thereof. Thus, pharmacopoeial standards are secondary standards; they may be drawn up only after approval of innovator products and only based the data generated by their manufacturers. It is not appropriate to prepare monographs based on dissertations/theses without original product MAA dossier data, including complete information on non-clinical and clinical characteristics. The main objective of the pharmacopoeial process is to improve test methods so that they are reproduced with acceptable precision in any laboratory, not only in original manufacturer’s laboratory(ies). The purpose of the process is to provide universal quality control tools for quality control laboratories and generic/hybrid or biosimilar product manufacturers. The pharmacopoeial monograph may not be created without access to the appropriate parts of innovator product MAA dossier.
Where adequate scientific justification is provided, tests and test methods may be replaced by alternative ones if they ensure equivalent or higher level of quality of a material concerned. Thus, where robust data demonstrate that non-compendial test methods render a better quality control (or, for example, are more efficient), compendial methods may be replaced by such alternative test procedures [4,18]. Therefore, there is another justified reason when non-compliance with official pharmacopoeial standards where such differences are well supported.
A specification may contain a smaller number of tests and test methods where the quality of a products is ensured by other means such as:
Real-time release testing/parametric release
Replacement of end product test by in-process testing
Both options may be considered within quality-by-design approach which is a new concept in pharmaceutical manufacturing and quality control [6,19,20,21]. It became a generally accepted approach in the pharmaceutical industry .
Thus, where adequately justified, a specification may contain a smaller number of tests than prescribed by the monograph; however, the overall quality should be assured using other tools and approaches.
It is also worth discussing general pharmacopoeial methods. Pharmacopeias contain a description of well-established methods and approaches to quality control; pharmaceutical development is not covered by pharmacopoeial texts. Therefore, it is important to understand that pharmacopeias are not intended to create completely new products. The new approaches are described in scientific guidelines of regulatory authorities, such as EMA, FDA, in ICH and WHO guidance documents, but the primary source of this information is the manufacturer’s own data and scientific literature. These approaches and methods are not usually standardized to the extent required by the pharmacopoeial regulations.
Many Russian pharmaceutical industry professionals think that pharmacopeias are an invariable source of knowledge on the drug product quality which should be complied with regardless of anything. In particular, this point of view is taught in pharmaceutical educational institutions. However, this approach is unreasonably narrow, especially in the case of development of innovative products. For this very reason, developing a specification (or an ND) based solely on pharmacopoeial texts does not yield the optimal level of quality, and in some cases, where pharmacopoeial texts are not substantiated by solid scientific experimental data, it might contradict to its ultimate purpose. Moreover, information included in pharmacopeias should not be considered sufficient for quality control without such aspects as GMP, process validation and characterization of all materials and processes used.
As for Russian State Pharmacopoeia, methodological drawbacks should be recognized since there are no formal procedures for developing and reviewing of pharmacopoeial texts, quality assurance approaches, and rules on how to use the Pharmacopoeia similar to that of Ph. Eur. or USP. In particular, Russian pharmaceutical legislation does not directly link pharmacopoeial monographs and specifications/NDs.
This is why developing an ND based on current principles of preparing and managing the Pharmacopoeia (or lack thereof) even more alienates it from the patient needs and actual manufacturing process.
Having discussed the links between pharmacopeias and NDs, let’s consider the place of an ND within a MAA dossier.
Normative document, marking authorization application dossier, and assessment procedure
As mentioned previously, before 2016 (i.e. before CTD format was enacted), an ND was the main document describing finished product quality control (and nothing else) to the prejudice of other armamentarium provided by the pharmaceutical quality system. The size of the document was limited to 50 to 70 pages on average, being no more than 20 to 30 pages in some cases. At the same time, the quality module in CTD format takes several thousands of pages; the major part of this is the description of test results and validation documentation, i.e. experimentally generated data.
Such brevity cannot enable the achievement of the main goals of the quality information provided in a MAA dossier which consists in the assessment of evolution and correctness of pharmaceutical, non-clinical, and clinical development carried out, including choice of manufacturing conditions and quality control strategies, in identification of risks related to manufacturing and use of a medicinal products, and in verification that all risks have been sufficiently characterized and assessed by the applicant within appropriate tests and investigations, as well as that all identified risks were either minimized or are under adequate control using appropriate tools.
Furthermore, based on the review of the term ‘quality,' it might be concluded that the quality is recognized after direct or indirect evaluation of safety and efficacy data. Thus, when the correlation between physicochemical/biological characteristics and clinical parameters had not been demonstrated during the development, it is unacceptable to claim that the quality of a medicinal product was demonstrated based only such characteristics which do not correlate with clinical data. Therefore, a ND developed arbitrarily (at least to some extent) cannot be used as a quality control tool because tests and test methods included therein were not derived based on non-clinical/clinical studies data (for instance, correlation between clinical efficacy and acceptable variability of potency) and process validation studies and were not correlated with each other.
The main part of an ND examination and the quality assessment at large within the MAA procedure consists of laboratory verification of analytical methods described in the ND. Laboratory verification (sometimes not quite correctly called as examination of method reproducibility) is acceptable tool for quality control purposes only in circumstances where test method are justified and validated (at least at the level of intermediate precision), and tests to be controlled and respective acceptance criteria were chosen adequately and are sufficient that appropriate (or at least minimal) level of quality control will be achieved taking into account other quality assurance methods used within the quality control system. In this light, it is inappropriate when some assessors request the improvement of analytical methods or exclude/include tests based on capabilities of the official control laboratories. Furthermore, interlaboratory validation of such ‘improved’ test methods will not be carried out because assessors’ requests for improvement of test methods are based on elaboration of a specification (being part of an ND) to comply with the capabilities of a single laboratory which is under auspices of the regulatory authority, so the needs of the whole network of official quality control laboratories are not taken into account.
It should be noted that in accordance with Article 14(2)(2) FL-61, the quality assessment is an evaluation of proposed medicinal product quality control test methods and submitted samples of the medicinal product using these methods. Therefore, the assessment of any other document included in the MAA dossier is an assessment of benefit/risk balance. The latter, however, is justified and corresponds to the globally accepted approaches to the assessment.
The illustration of an unreasonable requirement commonly set forth by the regulatory authority is the obligatory inclusion of an abnormal toxicity/general safety test into an ND of the majority of biological products and, in some instances, chemical drug products. Historically, this requirement was instituted due to the failure of the test which was carried out by the regulatory authority on its own motion, but the methods included in an ND were passed successfully.
An abnormal toxicity test is rather nonspecific and insensitive. It was developed in early 1900 to measure phenol levels in serum products and to quantify tetanus toxin in antiserums . However, state-of-the-art analytical techniques and manufacturing in GMP environment allow detecting impurities/adventitious matter without the need to use such a nonspecific safety test which necessitates to arrange a vivarium by the manufacturer and to slaughter unreasonable large numbers of animals . In this case, conforming with an ND but failing the abnormal toxicity test indicates that the ND was inadequately established because it did not possibly include appropriate specific tests and analytical methods. However, generally speaking, we might conclude that the quality control strategy was erroneous and was not based on solid scientific principles.
Currently, an abnormal toxicity test is used abroad for the batch release testing purposes very rarely. For example, as early as in 1998 the Commission of the European Pharmacopoeia made a decision to perform this test only at the beginning of manufacturing a product using a commercial process or where the process was subject to significant changes. At the moment, efforts are being taken to remove the requirements for a test for abnormal toxicity from 49 monographs of the Ph. Eur.  and even to exclude this test from the pharmaceutical quality control armamentarium .
When discussing a relationship between an ND and MAA dossier/assessment, it is also critical to bring to light the correlation between the ND and manufacturing of pharmaceutical products. These aspects also closely linked to manufacturing inspections.
Normative document vis-a-vis manufacturing/inspection
Before embarking on a discussion of the relationship between an ND and manufacturing/inspection, it is worth comparing objectives of site inspections and the MAA dossier assessment.
The objectives of the MAA dossier assessment and inspections are different. The former as mentioned above is performed to evaluate adequacy and completeness of the development carried out by the sponsor/manufacturer regarding process/product development and establishment of the quality control strategy, rationale and appropriateness thereof (from the patients/consumers point of view). The focus of the assessment is pharmaceutical development and the logic behind it, and inspections are intended to direct evaluation of commercial process (including quality control arrangements) at the site of manufacturing and of the adequacy of control methods. The objectives of inspections are derived from the definition of GMP. GMP means the part of quality assurance which ensures that products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use .
A MAA dossier is drawn up primarily to allow the assessment to be carried out, so the MAA dossier contains an only principal high-level description of the manufacturing process of both the active substance and finished product (CTD sections 3.2.S.2 and 3.2.P.3, respectively). Furthermore, the process description for other materials such as excipients, container closure materials, pre-starting materials is not described in the MAA dossier. However, GMP inspectors may examine these processes since they are authorized to supervise any party involved in the manufacture of the finished medicinal product. Assessment of manufacturing process of these materials is not needed because they are indirectly characterized during pharmaceutical development studies.
Since the goals of site inspections differ from those assessed during the authorization procedure, the documents that are evaluated during an inspection are not limited to the MAA dossier. Specifically, the MAA dossier helps inspectors to evaluate complying with conditions approved in the MAA dossier such as manufacturing address, obligation of each party involved, general process and in-process controls chart, the equipment used (where a dossier is in CTD format; a pre-2016 dossier contains very limited information which is of value for an inspection). Examination of documents and records within inspection is focused on those that are located at the manufacturing site. They include Site Master File, Manufacturing Formula and Processing Instructions, protocols, technical agreements, CoAs, reports, specifications for various materials and equipment, and other documents described in the GMP Guide chapter . The volume of these documents hundreds and thousands of time larger than the Quality Module of the MAA, not mentioning the pre-2016 MAA dossier.
On the other hand, the MAA dossier contains the description of the manufacturing process development (including laboratory-level manufacturing) and validation whereas an inspection is carried out to supervise the actual commercial manufacturing of a product placed on the market or used in clinical trials. An inspection is not focused on the adequacy of process development and validation (However, compliance with the validation protocol is within the scope of the inspection.) The aim of an inspection is to verify that process is arranged to comply with the principles and guidelines of GMP which are based on ISO 9000 dedicated to quality management standards.
Since an inspector is a government official who enforces manufacturers to comply with the marketing authorization (and manufacturing authorization) conditions which include an ND, he/she should ensure that batch release is carried out in accordance with such an ND, even where the final version of the document is not related to the actual manufacturing process and patient needs (see above). However, during the inspection process, the common sense should be used rather than the unreasonable following of contradictory rules and provisions.
At the same time beginning with 2016 according to FL-61 as amended, an ND is designated as an administrative document, i.e. it does not belong to chemical, pharmaceutical, and biological documentation in Module 3 . It is important to note that FL-61 does not lay down a requirement to use an ND for batch release testing. This is consistent with the requirements for the chemical, pharmaceutical, and biological documentation section of a MAA dossier (which corresponds to Module 3) where specifications are mentioned. Furthermore, the place of an ND in the pharmaceutical quality system becomes even vaguer since specifications were introduced into a MAA dossier. Therefore, it would be useful to limit the use of an ND to the official quality control by the government laboratories which do not have access to the appropriate parts of the MAA dossier of specific medicinal products. Thus, an ND should be a compilation of some quality control information submitted in the MAA dossier.
Regulatory support for the ND or specification management is not limited only to granting a marketing authorization. A specification is a document which is used as a reference standard for batch release testing, and it is subject to improvement and lifecycling in accordance with generally accepted scientific methods. Amendments to the specification should occur more frequently at the beginning of marketing a product, i.e. during the initial stage of gaining manufacturing and quality control experience [5,28].
Improvement of the quality control strategy, including specifications, is not mandatory for marketing/manufacturing authorization holders in Russia yet (however, this provision is envisaged in EAEU pharmaceutical legislation.) At the same time, the principle of continued improvement of manufacturing and quality control methods based on scientific and technical progress is a legal requirement in foreign jurisdictions. For instance, Article 23(1) of Directive 2001/83/EC reads: ‘After a marketing authorisation has been granted, the marketing authorisation holder shall, in respect of the methods of manufacture and control provided for in the marketing authorization application, take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.’ . This provision covers GMP, pharmacopoeial tests, new scientific approaches, etc.
In summary, an ND is a domestic invention (which was accepted by some neighboring countries). Its aim was the official quality control of imported medicinal products. Subsequently, the scope of an ND increased and began to claim the one-size-fits-all tool in quality control to the prejudice of other methods of the pharmaceutical quality system. However, in the absence of a solid scientific methodology for drawing up of this document and when it is used for batch release testing using current principles, an ND threatens public health and interferes with the integrated approached to the quality assurance and quality control.
It is obvious that quality control tools need to be harmonized with the generally accepted methodologies. The efforts create a single market within EAEU, including the pharmacopeial harmonization, plays an important role for such harmonization. We think, however, that the key emphasis should be given to the education and training of industry professionals (primarily in the area of pharmaceutical engineering and analytics) which are based on the state-of-the-art approaches to manufacturing and quality control of medicinal products.
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