EMA, the European Commission and Heads of Medicines Agencies (HMA) have phased out the extraordinary regulatory flexibilities for medicines put in place during the COVID-19 pandemic to help address regulatory and supply challenges arising from the pandemic.
This follows the end of the COVID-19 public health emergency declared by WHO in May .
On-site GMP and GDP inspections have restarted after being postponed or carried out remotely during the pandemic.
However, a considerable number of postponed inspections still need to be carried out.
The validity of GMP and GDP certificates was extended until the end of . The GMP/GDP Inspectors Working Group has decided to continue the extension of the validity date until or the conclusion of the next on-site inspection, whichever comes first, except where clarifying remarks in the document state otherwise.
Meanwhile, competent authorities will perform risk-based supervision of sites, either by on-site inspections or distant assessments, and based on the outcome may continue to issue, withdraw or restrict GMP and GDP certificates, as appropriate.
The inspections will be prioritised based on risk, so that the highest priority manufacturers, such as manufacturers of sterile product and biological products, and wholesale distributors are inspected first. In addition, inspections will be prioritised depending on the date of the last inspection.
Questions about the validity date of a GMP or GDP certificate should be addressed to the competent authority that issued the certificate.
It is incumbent upon manufacturers, importers and distributors to continue complying with GMP and GDP as appropriate.
Supervisory authorities will remain vigilant to ensure the quality of medicines that are made available to patients in the EEA.
Inspections (including distant assessments) may be carried out at any time. In case of serious non-compliance, appropriate regulatory actions will be triggered.
The guidance was agreed by the GMP/GDP Inspectors Working Group coordinated by EMA. It will be updated when there is additional information available.
Quality assurance is a broad concept that includes all matters that individually or collectively influence the quality of a product, that is, management of the quality of raw materials, products and other components, services related to production, and management, production and inspection processes. It is applied in pre-production to verify what will be made meets specifications and requirements and also while manufacturing production. Two principles included in quality assurance are: fit for purpose' where the product should be suitable for the intended purpose; and 'right first time' mistakes should be strongly eliminated. In order to achieve quality, there must be a system of comprehensive quality assurance and implemented it correctly. This last issue include the management of GMP, quality control and quality risk.[ 1 , 24 , 25 ]
This guideline describes a comprehensive model for an effectiveness quality system of medicinal products, based on the concepts of ISO quality and its implementation throughout all stages of the life cycle of the product. This guideline will growth the technological innovation and strengthening of the link between pharmaceutical development and manufacturing activities. The guideline applies to supporting the development and manufacture of substances of Pharmaceutical Industry, Active Pharmaceutical Ingredient and medicinal products, including biotechnology and biological products throughout the life cycle of the product.[ 1 , 22 , 23 , 24 , 25 , 26 , 27 ]
According to EC GMP, the management of an enterprise should determine and provide adequate and appropriate resources such as human resources, financial, materials, facilities and equipment to implement and maintain the Quality Management System and improve effectiveness. Effective coordination and management of human resources are key factors in the proper functioning of any enterprise. To this end, enterprise management has duties and responsibilities in staff recruitment as well as the delegation of tasks.[ 1 , 28 , 29 , 30 , 31 ]
Premises and equipment must meet and comply with all rules, according to the operations to be performed in order to minimize the risk of errors and should allow effective cleaning and maintenance.[ 1 , 32 , 33 , 34 ]
Good documentation constitutes an essential part of the quality assurance system and it is the key to operate in compliance with GMP requirements.[ 1 , 35 ] All types of documents and media used should be fully defined in the manufacturer's Quality Management System. Documentation may exist in several forms (paper-based, electronic or photographic media). The objectives of the system of documentation must be to establish, monitor and record all activities with impact on all aspects of the quality of medicinal products.[ 1 , 35 , 36 , 37 ]
Production operations must clearly follow the procedures. They must comply with the principles of GMP in order to obtain quality products and be in accordance with the relevant manufacturing and MA. Production should be performed and supervised by competent people. All handling of materials and products, such as reception and quarantine, sampling, storage, labeling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and where necessary, recorded.[ 1 , 38 , 39 ]
Quality control is concerned with sampling, specifications and testing as well as the organization, documentation and release procedures which ensure that the required and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory.[ 1 , 40 , 41 ] Quality control is not confined to laboratory operations, but must be involved in all decisions that may concern the quality of the product. The independence of quality control from production is considered fundamental to the satisfactory operation of quality control.[ 1 , 40 , 41 , 42 ]
The preparation and analysis of contracts must be correctly set, agreed and controlled in order to avoid misunderstandings, which may result in an unsatisfactory quality of a product or work.[ 1 , 43 , 44 , 45 ]
The guidelines that regulate the contract and analysis manufacturing describe the responsibilities of manufacturers towards the competent authorities of the member states with respect to the granting of MA and manufacturing authorizations. The introduction of guidance on the Activities Subcontracting is based on the Pharmaceutical Quality System of the ICH Q10 document in order to provide updated guidance on subcontracting activities regulated by GMP, beyond the current scope of operations of the contract manufacture and analysis.[ 1 , 43 ]
In accordance with Article 117 of Directive /83/EC, Article 84 of Directive /82/EC and the WHO, a system should be designed to recall, if necessary, promptly and effectively products known or suspected to be defective from the market. The procedures should include procedures for evaluation by the Quality Control Unit.[ 1 , 46 , 47 , 48 , 49 ]
The objectives of self-inspections are the evaluation and supervision of compliance of the manufacturer with GMP in all aspects of production and quality control. It must be designed to detect any deficiency in the implementation of GMP and to recommend corrective procedures.[ 1 , 50 , 51 , 52 ]
It is noted that the guidelines of GMP does not cover safety aspects for the personnel engaged in the manufacture, nor aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by other parts of the legislation. At the same time, these guidelines are not intended to define registration requirements or modify pharmacopoeia requirements and do not affect the ability of the responsible competent authority to establish specific registration requirements regarding active substances within the context of MA/manufacturing authorizations. All commitments in registration documents must be met. These guidelines apply to the manufacture of active substances for medicinal products for human use and to the manufacture of sterile active substances only up to the point immediately prior to the active substance being rendered sterile. Although the sterilization and aseptic processing of sterile active substances are not covered, those issues should be performed in accordance with the principles and guidelines of GMP, as defined by local authorities, including active substances that are produced using blood or plasma as raw materials, in spite of excluding whole blood and plasma as there are other detailed technical requirements for the collection and testing of blood. It should be noted that these guidelines do not apply to bulk-packaged medicinal products.[ 1 , 55 , 56 , 57 , 58 ]
The members of the ICH developed a guideline denominated Q7A. This guideline is intended to provide guidance regarding GMP for the manufacture of active substances under an appropriate system for managing quality. It is also intended to ensure that active substances meet the requirements for quality and purity that they purport or are represented to possess.[ 1 , 53 , 54 , 55 , 56 ]
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Since this type of medicinal products is particularly susceptible to microbial contaminants and other contaminants during manufacturing, it is necessary to follow preventive procedures and it should be a priority for the manufacturer MA holder.[1,59,60]
The manufacture of sterile products requires special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination, being highly dependent on knowledge, training and attitudes of the personnel involved. This type of manufacture must strictly follow methods and preparation processes, carefully established and validated, since the quality assurance, is of particular importance. The manufacture of sterile products should occur in clean areas whose access must be achieved through airlocks for personnel and/or equipment and materials.[1,61,62,63,64,65,66]
The methods employed in the manufacture of biological active substances and biological medicinal products for human use are critical factors in shaping the appropriate regulatory control, because the manufacture of these involves certain specific, considerations arising from the nature of products and manufacturing processes, being necessary take some special precautions. Unlike conventional medicinal products, which are normally produced and controlled using reproducible chemical and physical techniques, biological products are manufactured through methods that involve biological processes and materials, such as cultivation cells or extraction of material from living organisms. These biological processes may exhibit inherent variability and hence, that the range and nature of the by-products may be variable.[1,67,68,69]
Radiopharmaceuticals must be manufactured and handled with some special care. The regulatory procedures necessary for the control of radiopharmaceuticals are determined in large part by the sources of these products and the production methods. The level of risk depends essentially on the types of radiation emitted and the half-lives of radioactive isotopes. It is necessary to pay special attention to the cross contamination, the contaminant of radioactive isotopes and to waste disposal. Due to its short half-life, some radiopharmaceuticals are released and administered to the patients after their production, before completing all quality control tests. The EC guideline is applied to manufacturing procedures employed by industrial manufacturers, Nuclear Centers/Institutes and positron emission tomography (PET) Centers for the production and quality control of the following types of products: Radiopharmaceuticals, PET radiopharmaceuticals, Radioactive Precursors for radiopharmaceutical production and lastly Radionuclide Generators.[1,70,71,72]
The International Atomic Energy Agency is the agency that regulates the transport of radiopharmaceuticals and the requirements for protection against radiation.[1,70,72]
The manufacture of pressurized aerosols for inhalation with metering valves, according to the GMP guidelines of the EC/EEA, requires a special consideration mainly due to the particular nature of these dosage forms. These medicinal products must be manufactured under conditions that minimize microbial and particulate contaminations. The quality assurance is fundamental for components with valve and to the uniformity of suspensions.[1,73,74]
At the level of EC/EEA, the gases meet the definition of medicinal products of Directive /83/EC (designated medicinal gases) are subject to the requirements of this Directive, including the manufacturing requirements addressing the manufacture of active substances gases and medical gases. In this respect, these guidelines deal with the manufacture of active substances from gases and the manufacture of medicinal gases. The delineation between the manufacture of active substances and the manufacture of medicinal products should be clearly defined in each MA dossier. The manufacture of active substances from gases must comply with the basic requirements for active substances used as starting materials and other guidance when needed.[1,75,76]
This class of medicinal products should be produced in accordance with the principles and GMP. Procedures need to be flexible as the process increases, and it should be appropriate to the stage of development of the product. It is noted that an increase in complexity in manufacturing operations requires a highly effective quality system.[1,77,78,79]
The requirements for the collection, testing and quality control of medicinal products derived from human blood or plasma are defined by a system of quality assurance, based on the existence of a national structure which is independent of manufacturers, complying with the principles and guidelines of GMP. Those products are considered to be biological medicinal products due to their specific characteristics and the starting materials include biological substances, such as cells or fluids (including blood or plasma) of human origin. The provisions of CE apply to medicinal products derived from human blood or plasma, fractionated in or imported into the EU/EEA. Furthermore, apply to the starting material (e.g., human plasma) for these products and for stable derivatives of human blood or human plasma (e.g., albumin) incorporated into medical devices. However, it does not apply to blood components intended for transfusion.[1,80,81]
The procedures and techniques used in the manufacture and quality control of herbal medicines are often substantially different from those used for conventional medicinal products. The herbal substance should be of suitable quality. The supporting data should be provided to the manufacturer of the herbal preparation/herbal medicinal product. A consistent quality assurance of herbal substances requires more detailed information on its agricultural production.[1,82,83,84]
These guidelines apply to all herbal starting materials: Medicinal plants, herbal substances or herbal preparations.[1,82,83]
In accordance with the guidelines of GMP of the EC/EEA, a MA for a product which includes irradiation as part of its processing should also refer to the note produced by the Committee for Proprietary Medicinal Products.[1,85]
Ionizing radiation can be used during the manufacturing process for various purposes; it may be made by pharmaceutical manufacturer or an operator of a radiation facility under contract both of whom must hold an appropriate manufacturing authorization.[1,85,86]
Sampling is an operation where a small fraction of the batch is removed integrating operations to select a portion of a pharmaceutical product for a specific purpose, in accordance with an appropriate procedure. This process should be carried out in accordance with written and approved procedures that are appropriate to the sample and the type of control intended to be applied to the sample and the sample material.[1,87,88,89]
The EC through Annex 11 of GMP and FDA through the US 21 CFR Part 11 describes the requirements to be followed for computerized systems, electronic records and digital signatures.[1,90,91]
These guidelines apply to all forms of computerized systems used as part of the activities regulated by the GMPs. These systems are a set of software and hardware components, which collectively satisfy certain functionalities. There should be no decrease in product quality, process control or quality assurance, where the quality system is replaced by manual operations.[1,90,92]
Food and Drug Administration has established criteria by which electronic records, electronic signatures, and handwritten signatures executed to electronic records are trustworthy, reliable and generally equivalent to paper records and handwritten signatures executed on paper.[1,91,93]
The guidelines of GMPs qualification and validation of the EC/EEA describes the principles of qualification and validation which are applied in the manufacture of medicinal products. In these requirements, manufacturers identify what validation work needed to prove control of the critical aspects of their particular operations.[1,94,95]
The guidelines of the EC/EEA are a guide of GMP to holders of medicinal products with MA or for export. It also covers cases where the batch had different stages of production or test conducted at different locations or by different manufacturers, and where an intermediate or bulk production batch is divided into more than one finished product batch. The release of batches that were imported into the EC/EEA are also included in the domain of these guidelines, when there is and when there is no mutual recognition agreement between the EC/EEA and third countries. Investigational Medicinal Products are also under these guidelines.[1,96]
Parametric release is a system of release that provides assurance that the product is of the intended quality based on information collected during the manufacturing process and in accordance with specific GMP requirements, annexes and related guidelines. However, it does not mean that all tests specified should be executed in the finished product before release.[1,97,98,99,100]
EU guidelines, refers only to part of parametric release that deals with the routine release of finished products without carrying out a sterility test. According to these guidelines, the implementation of parametric release is in line with the European Pharmacopoeia.[1,97,98,100]
The PIC/S guidelines seek covers a wide scope that includes a reduction or elimination of finished products routine testing. These guidelines are not intended to be a barrier to technical innovation. Recommendations are not mandatory for the industry, but the latter should regard them as appropriate.[1,99]
Food and Drug Administration provides recommendations to applicants on the information to be included as support of parametric release for sterile products terminally subjected to sterilization by moist heat, at the time of submission of a new medicinal product. Currently, this agency requires that sterile products meet certain requirements for sterility before release to the market.[1,101]
At the level of EC/EEA, the guidelines provided and prepared by the relevant organisms in this scope offer guidance on the taking and holding of reference samples of starting materials, packaging materials or finished products and retention samples of finished products. These guidelines also include guidelines on the collection and retention of samples of medicinal products for parallel import and distribution. Samples are retained in order to meet two objectives: First, to provide a sample for analytical testing; second, to provide a sample of the totally finished product. Samples are divided into two categories: Reference sample and retention sample.[1,102,103]
About guidance on Quality Risk Management, ICH Q9 document containing guidelines on GMP to be followed in this context was elaborated. This guideline specifically provides principles and examples of tools of Risk Quality that can be applied to all aspects of pharmaceutical quality including the development, manufacture, distribution and inspection processes and submission/review of the entire life cycle of substances, medicinal products, biologics and biotechnology products including the development, manufacture, distribution and inspection and submission/review of the entire life cycle of substances, medicinal products, biologics and biotechnology products, including the use of starting materials, solvents, excipients, packaging and labeling materials, that allow for more effective and consistent risk-based decisions, either by regulators or the Industry. It is not intended to create new expectations beyond current requirements. The purpose of this guideline is to provide a systematic approach of quality risk management and serves as a base or resource, independent, supporting other documents relating to the quality of ICH and complements existing quality practices, requirements, standards and guidelines in the scope of Pharmaceutical Industry and regulatory environment, thus remaining optional character.[1,104,105,106,107,108,109]
Quality risk management can be applied not only in the manufacturing environment, but also in connection with the pharmaceutical development and preparation of quality part of the dossier for MA. The guidelines also apply to regulatory authorities in the field of pharmaceutical evaluation of the quality of the dossier for MA, GMP inspections and treatment of suspicions of quality defects.[1,22,107,108,109]
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