ICH Guidelines For Quality Control Of Herbal Drugs: ICH-international council for harmonization of technical requirements for pharmaceuticals for human use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH’s mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. Harmonization achievements in the quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing, and a more manufacturing practice (GMP) risk management.
Q1A Stability Testing of New Drugs Substances And Products
Approvals are given by the steering committee of the second revision directly under step 4 without further public constitution to include consequences of the adoption of QIF (stability data package for registration applications in climatic zone 3&4) and recruitment for adoption to the 3 ICH regulatory bodies. The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States. It does not seek necessarily to cover the testing for registration in or export to other areas of the world.
The guideline seeks to exemplify the core stability data package for new drug substances and products but leaves sufficient flexibility to encompass the variety of different practical situations” that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons. The guideline addresses the submitted registration applications for new information to be molecular entities and associated drug products. This guideline does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc.
Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline.
choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan, and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, 1-IV. This guideline addresses climatic zones I and II. The principle has been established that stability information generated in any one of the three regions of the EC, Japan, and the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guideline and the labeling is in accord with national/regional requirements.
Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation.
- Stress testing.
- Selection of batches
- Container closure system
- Testing frequency
- Storage condition
- Stability commitment
- Statements / labeling
The design of the formal stability studies for the drug product should be based on knowledge of the behavior and properties of the drug substance and from stability studies on the drug substance and experience gained from clinical formulation studies. The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated Includes
- Photostability testing.
- Selection of batches.
- Container closure system.
- Testing frequency.
- Storage conditions.
- Stability commitment.
The purpose of this is to outline the changes made in Q1A(R) that result from the adoption of ICH QIF “Stability Data Package for Registration Applications in Climatic Zones III and IV”.
These changes are:
1. The intermediate storage condition has been changed from 30 °C 2 °C/60% RH+5% RH to 30 C+2 °C/65% RH 5 RH in the following sections:
Drug Substance-Storage Conditions – General Case
Drug Product – Storage Conditions – General Case
Drug products packaged in semi-permeable containers
2. 30 °C+2 °C/65% RH+55 RH can be a suitable alternative long-term storage condition to 25 °C+2 PC/60% RH15% in the following sections:
Drug Substance-Storage Conditions – General Case
Drug Product – Storage Conditions – General Case
3. 30 °C+2 °C/35% RH45% RH has been added as a suitable alternative long-term storage condition to 25 °C+2 °C/40% RH+5% and the corresponding example for the ratio of water-loss rates has been included in the following section:
Drug products packaged in semi-permeable containers
4. Mid-stream switch of the intermediate storage condition from 30 °C °C/60% RH15% RH to 30 C:2 °C/65% RH-5% RH can be appropriate provided that the respective storage conditions and the date of the switch are documented and stated in the registration application. It is recommended that registration applications contain data from complete studies at the intermediate storage condition 30°C+2 °C/65% RH+5% RH, if applicable, by three years after the date of publication of this revised guideline in the respective ICH tripartite region.
Q1B Stability Testing
Photostability testing of new drug substances and products
The ICH harmonized tripartite guidelines covering the stability testing of new drug substances and products (hereafter referred to as the Parent Guideline) notes that light testing should be an integral part of stress testing. This document is an annex to the Parent Guideline and addresses the recommendations for photostability testing.
Drug substances and drug product
- Presentation of samples
- Analysis of samples
- Judgment of results
An immediate (primary) pack is that constituent of the packaging that is in direct contact with the drug substance or drug product and includes any appropriate label. The marketing pack is the combination of the immediate pack and another secondary packaging such as a carton.
Forced degradation testing studies are those undertaken to degrade the sample deliberately. These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation.
Confirmatory studies are those undertaken to establish photostability characteristics under standardized conditions. These studies are used to identify precautionary measures needed in manufacturing or formulation and whether light-resistant packaging and/or special labeling is needed to mitigate exposure to light. For the confirmatory studies, the batches should be selected according to batch selection for long-term and accelerated testing which is described in the Parent Guideline
Q1C Stability testing for new dosage form
The ICH harmonized tripartite guideline on stability testing of new drug substances and products was issued on October 27, 1993. This document is an annex to the ICH parent stability guideline and addresses the recommendations on what should be submitted regarding the stability of new dosage forms by the owner of the original application, after the original submission for new drug substances and products.
New dosage form
A new dosage form is defined as a drug product that is a different pharmaceutical product type but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority.
Such pharmaceutical product types include products of different administration routes (e.g., oral to parenteral), new specific functionality/delivery systems. (e.g., immediate-release tablet to modified-release tablet) and different dosage forms of the same administration route (e.g., capsule to tablet, suspension solution).
Q1D Bracketing And Matrixing Designs For Stability Testing New Drug Substances And Products
This guideline is intended to address recommendations on the application of bracketing and matrixing to stability studies conducted by principles outlined in the ICH Q1A(R). Harmonized Tripartite Guideline on Stability Testing of New Drug Substances and Products thereafter referred to as the parent guideline).
This document guides bracketing and matrixing study designs. Specific principles are defined in this guideline for situations in which bracketing or matrixing can be applied.
A full study design is one in which samples for every combination of all design factors are tested at all times points. A reduced design is one in which samples for every factor combination are not all tested at all times point. A reduced design can be a suitable alternative to a full design when multiple design factors are involved. Any reduced design should have the ability to adequately predict the retest period or shelf life. Before a reduced design is considered, certain assumptions should be assessed and justified. The potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the reduced amount of data collected.
As defined in the glossary to the parent guideline, bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (eg, strength, container size, and/or fill) are tested at all times point as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.
The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes.
Bracketing can be applied to studies with multiple strengths of identical or closely related formulations Examples include but are not limited to capsules of different strengths made with different fill plug sizes from the same powder blend, tablets of different strengths manufactured by compressing varying amounts of the same granulation, and oral solutions of different strengths with formulations that differ only in minor excipients (eg., colorants, flavorings).
With justification, bracketing can be applied to studies with multiple strengths where the relative amounts of drug substance and excipients change in a formulation. Such justification can include a demonstration of comparable stability profiles among the different strengths of clinical or development batches.
In cases where different excipients are used among strengths, bracketing generally should not be applied.
As defined in the glossary of the parent guideline, matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems.
When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems.
Each storage condition should be treated separately under its matrixing design Matrixing should not be performed across test attributes. However, alternative matrixing designs for different test attributes can be applied if justified.
Matrixing designs can be applied to strengths with identical or closely related formulations Examples include but are not limited to capsules of different strengths made with different fill plug sizes from the same powder blend,
tablets of different strengths manufactured by compressing varying amounts of the same granulation, and oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colorants or flavorings).
Other examples of design factors that can be matrixes include batches made using the same process and equipment, and container sizes and/or fills in the same container closure system. With justification, matrixing designs can be applied, for example, to different strengths where the relative amounts of drug substance and excipients change or where different excipients are used, or to different container closure systems. The justification should generally be based on supporting data. For example, to matrix across two different closures or container closure systems, supporting data could be supplied showing relative moisture vapor transmission rates or similar protection against light. Alternatively, supporting data could be supplied to show that the drug product is not affected by oxygen, moisture, or light
Q1E Evaluation of stability data
This guideline is intended to provide recommendations on how to use stability data generated by the principles detailed in the ICH guideline “Q1A(R) Stability Testing of New Drug Substances and Products” (hereafter referred to as the parent guideline) to propose a retest period or shelf life in a registration application. This guideline describes when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by “available data from the stability study under the long-term storage condition” (hereafter referred to as long-term data). The guidance on the evaluation and statistical analysis of stability data provided in the parent guideline is brief and limited in scope. The parent guideline states that regression analysis is an appropriate approach to analyzing quantitative stability data for the retest period of shelf life estimation and recommends that a statistical test for batch pool ability be performed using a level of significance of 0.25. However, the parent guideline includes few details and does not cover situations where multiple factors are involved in a full- or reduced-design study.
This guideline is an expansion of the guidance presented in the Evaluation sections of the parent guideline.
This guideline addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and associated drug products. The guideline provides recommendations on establishing retest periods and shelf lives for drug substances and drug products intended for storage at or below “room temperature”. It covers stability studies using single-or multi-factor designs and full or reduced designs.
Note: The term “room temperature” refers to the general customary environment and should not be inferred to be the storage statement for labeling. ICH Q6A and Q6B should be consulted for recommendations on the setting and justification of acceptance criteria and ICH QID should be referenced for recommendations on the use of full versus reduced-design studies.
The design and execution of formal stability studies should follow the principles outlined in the parent guideline. The purpose of a stability study is to establish, based on testing a minimum of three batches of the drug substance or product, a retest period or shelf life and label storage instructions applicable to all future batches manufactured and packaged under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within acceptance criteria throughout its retest period or shelf life.
Q2 (R1) Validation of analytical procedures
Text and methodology
This document presents a discussion of the characteristics for consideration during the validation of the analytical procedures included as part of registration applications submitted within the EC, Japan, and the USA. This document does not necessarily seek to cover the testing that may be required for registration in, or export to, other areas of the world. Furthermore, this text presentation serves as a collection of terms, and their definitions, and is not intended to provide direction on how to accomplish validation. These terms and definitions are meant to bridge the differences that often exist between various compendia and regulators of the EC, Japan the USA.
The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. A tabular summation of the characteristics applicable to identification, control of impurities, and assay procedures is included. Other analytical procedures may be considered in future additions to this document.
Types of analytical procedures to be validated
- The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedures: Identification tests;
- Quantitative tests for impurities’ content;
- Limit tests for the control of impurities;
- Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product.
Although there are many other analytical procedures, such as dissolution testing for drug products or particle size determination for drug substances, these have not been addressed in the initial text on the validation of analytical procedures. Validation of these additional analytical procedures is equally important to those listed herein and may be addressed in subsequent documents.
A brief description of the types of tests considered in this document is provided below.
- Identification tests are intended to ensure the identity of an analyte in a sample. This is normally achieved by comparison of a property of the sample (e.g., spectrum, chromatographic behavior, chemical reactivity, etc) to that of a reference standard;
- Testing for impurities can be either a quantitative test or a limit test for the impurity in a sample. Either test is intended to accurately reflect the purity characteristics of the sample. Different validation characteristics are required for a quantitative test than for a limit test;
- Assay procedures are intended to measure the analyte present in a given sample. In the context of this document, the assay represents a quantitative measurement of the major component(s) in the drug substance. For the drug product, similar validation characteristics also apply when assaying for the active or other selected component(s). The same validation characteristics may also apply to assays associated with other analytical procedures (e.g., dissolution).
The objective of the analytical procedure should be clearly understood since this will govern the validation characteristics which need to be evaluated. Typical validation characteristics which should be considered are listed below:
- Intermediate Precision
- Detection Limit
- Quantization Limit
Each of these validation characteristics is defined in the attached Glossary. The table lists those validation characteristics regarded as the most important for the validation of different types of analytical procedures. This list should be considered typical for the analytical procedures cited but occasional exceptions should be dealt with on a case-by-case basis. It should be noted that robustness is not listed in the table but should be considered at an appropriate stage in the development of the analytical procedure.
Furthermore, revalidation may be necessary for the following circumstances:
- Changes in the synthesis of the drug substance;
- Changes in the composition of the finished product;
- Changes in the analytical procedure.
The degree of revalidation required depends on the nature of the changes. Certain other changes may require validation as well
Q3A (R2) Impurities in new drug substances
This document is intended to guide registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances used during the clinical research stage of development. The following types of drug substances are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product, and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin.
Impurities in new drug substances are addressed from two perspectives:
Chemistry aspects include classification and identification of impurities, report generation, a listing of impurities in specifications, and a brief discussion of analytical procedures; and Safety aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies,
Classification of impurities
Impurities can be classified into the following categories:
- Organic impurities (process- and drug-related)
- Inorganic impurities
- Residual solvents
Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:
- Starting materials
- Degradation products
- Reagents, ligands, and catalysts
Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:
- Reagents, ligands, and catalysts
- Heavy metals or other residual metals
- Inorganic salts
- Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished (see ICH Guideline Q3C on Residual Solvents).
Excluded from this document are (1) extraneous contaminants that should not occur in new drug substances and are more appropriately addressed as Good Manufacturing Practice (GMP) issues (2) polymorphic forms, and (3) enantiomeric impurities.
Reporting impurity content of batches
Analytical results should be provided in the application for all batches of the new drug substance used for clinical, safety, and stability testing, as well as for batches representative of the proposed commercial process. Quantitative results should be presented numerically, and not in general terms such as “complies”, “meets limit” etc. Any impurity at a level greater than (>) the reporting threshold (see Attachment 1) and total impurities observed in these batches of the new drug substance should be reported with the analytical procedures indicated. Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results should be reported to one decimal place (e.g. 1.3%). Results should be rounded using conventional rules (see Attachment 2). Tabulation (e.g., spreadsheet) of the data is recommended Impurities should be designated by code number or by an appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully justified. All impurities at a level greater than (>) the reporting threshold should be summed and reported as total impurities. When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate validation information provided. Representative chromatograms should be provided. Chromatograms of representative batches from analytical validation studies showing separation and detectability of impurities (e.g. on spiked samp along with any other impurity tests routinely performed, can serve as the representative impune profiles. The applicant should ensure that complete impurity profiles (e.g., chromatogram individual batches are available if requested.
Tabulation should be provided that links the specific new drug substance batch to each safety study and each clinical study in which the new drug substance has been used. For each batch of the new drug substance, the report should include:
- Batch identity and size
- Date of manufacture.
- Site of manufacture
- Manufacturing process
- Impurity content, individual and total
- Use of batches
- Reference to the analytical procedure used
Listing of impurities in the specification
In summary, the new drug substance specification should include, where applicable, the following list of impurities:
- Organic impurities
- Each specified identified impurity
- Each specified unidentified impurity
- Any unspecified impurity with an acceptance criterion of not more than (D) the identification threshold
- Total impurities
Q3B (R2) Impurities in new drug products
This document guides registration applications on the content and qualification of impurities in new drug products produced from chemically synthesized new drug substances not previously registered in a region or member state.
This guideline addresses only those impurities in new drug products classified as degradation. products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system (collectively referred to as “degradation products” in this guideline). Generally, impurities present in the new drug substance need not be monitored or specified in the new drug product unless they are also degradation products.
Impurities arising from excipients present in the new drug product or extracted or leached from the container closure system are not covered by this guideline. This guideline also does not apply to new drug products used during the clinical research stages of development. The following types of products are not covered in this guideline For each batch of the new drug product described in the registration application, the documentation should include:
- Batch identity, strength, and size
- Date of manufacture
- Site of manufacture
- Manufacturing process
- Immediate container closure
- Degradation of product content, individual and total
- Use of batch (e.g., clinical studies, stability studies)
- Reference to the analytical procedure used
- Batch number of the drug substance used in the new drug product
- Storage conditions for stability studies
In summary, the new drug product specification should include, where applicable, the following list of degradation products:
- Each specified identified degradation product
- Each specified unidentified degradation product
- Any unspecified degradation product with an acceptance criterion of not more than the identification threshold
- Total degradation products.
Q3C (R5) Residual solvents
The objective of this guideline is to recommend acceptable amounts of residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends the use of less toxic solvents. and describes levels considered to be toxicologically acceptable for some residual solvents.
Q3D Guidelines for elemental impurities
Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (eg, through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: the evaluation of the toxicity data for potential elemental impurities; the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern; and application of a risk-based approach to control elemental impurities in drug products. An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDES established in this guideline are considered to be protective of public health for all patients populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity, thresholds have been shown to have an impact on other quality attributes of the drug product (eg. element catalyzed degradation of drug substances). In addition, for elements with high PDEs, other limits may have to be considered from a pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH Q3A).
This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.
The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (eg conjugates) are within the scope of this guideline, as are drug products containing synthetically produced polypeptides polynucleotide, and oligosaccharides.
This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialyzes solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This guideline does not apply to products based on genes (gene therapy), cells (cell therapy), and tissue (tissue engineering). In some regions, these products are known as advanced therapy medicinal products.
This guideline does not apply to drug products used during clinical research stages of development. As the commercial process is developed, the principles contained in this guideline can be useful in evaluating elemental impurities that may be present in a new drug product.
Application of QSD to existing products is not expected 36 months after publication of the guideline by ICH.
The factors considered in the safety assessment for establishing the PDE are listed below in approximate order of relevance:
- The likely oxidation state of the element in the drug product
- Human exposure and safety data when it provided applicable information:
- The most relevant animal study
- Route of administration:
- The relevant endpoints
Q4B Evaluation and recommendation of pharmacopeia texts for use in “ICH” regions
This document describes a process for the evaluation and recommendation by the Q4B Expert Working Group (EWG) of selected pharmacopeia texts to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH regions
Q5A (R1) Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin
This document is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin (ie, mammalian, avian, insect) and outlines data that should be submitted in the marketing application/registration package. For this document, the term virus excludes nonconventional transmissible agents like those associated with Bovine Spongiform Encephalopathy (BSE) and scrape. Applicants are encouraged to discuss issues associated with BSE with the regulatory authorities.
The scope of the document covers products derived from cell cultures initiated from characterized cell banks. It covers products derived from in vitro cell cultures, such as interferon’s, monoclonal antibodies, and recombinant DNA-derived products including recombinant subunit vaccines, and also includes products derived from hybridoma cells grown in vivo as ascites. In this latter case, special considerations apply and additional information on testing cells propagated in vivo is contained in Appendix 1. Inactivated vaccines, all live vaccines containing self-replicating agents, and genetically engineered live vectors are excluded from the scope of this document.
The risk of viral contamination is a feature common to all biotechnology products derived from cell lines. Such contamination could have serious clinical consequences and can arise from the contamination of the source cell lines themselves (cell substrates) or the adventitious introduction of the virus during production. To date, however, biotechnology products derived from cell lines have not been implicated in the transmission of viruses. Nevertheless, it is expected that the safety of these products about viral contamination can be assured only by the application of a virus testing program and assessment of virus removal and inactivation achieved by the manufacturing process, as outlined below.
Three principal, complementary approaches have evolved to control the potential viral contamination of biotechnology products:
- Selecting and testing cell lines and other raw materials, including media components, for the absence of undesirable viruses which may be infectious and/or pathogenic for humans;
- Assessing the capacity of the production processes to clear infectious viruses;
- Testing the product at appropriate steps of production for the absence of contaminating infectious viruses.
Q5B Quality of biotechnological products
This document presents guidance regarding the characterization of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells. This document is intended to describe the types of information that are considered valuable in assessing the structure of the expression construct used to produce recombinant DNA derived
Q5C Quality of biotechnological products
Stability testing of biotechnological/biological products
The guidance stated in this annex applies to well-characterized proteins and polypeptides, their derivatives and products of which they are components, and which are isolated from tissues, body fluids, cell cultures, or produced using rDNA technology. Thus, the document covers the generation and submission of stability data for products such as cytokines interferons. interleukins, colony-stimulating factors, and tumor necrosis factors), erythropoietin’s, plasminogen activators, blood plasma factors, growth hormones and growth factors, insulin, monoclonal antibodies, and vaccines consisting of well-characterized proteins or polypeptides. In addition, the guidance outlined in the following sections may apply to other types of products, such as conventional vaccines, after consultation with the appropriate regulatory authorities. The document does not cover antibiotics, allergenic extracts, heparins, vitamins, whole blood, or cellular blood components
Q5D Derivation and characterization of cell substrates
This guideline covers cell substrates having a cell banking system. In this document. “cell-substrate” refers to microbial cells or cell lines derived from human or animal sources that possess the full potential for the generation of the desired biotechnological/biological products for humans in vivo ex vivo use. Reagents for in vitro diagnostic use are outside the scope of this document. Animal sources of cell lines include all those of metazoan origin. Both continuous cell lines of indefinite in vitro lifespan and diploid cells of finite in vitro lifespan are included. Microbial sources include bacteria, fungi, yeast, and other unicellular life forms.
Q5E Comparability of biotechnological/biological products subject to changes in their manufacturing process
The objective of this document is to provide principles for assessing the comparability of biotechnological/biological products before and after changes are made in the manufacturing process for the drug substance or drug product. Therefore, this guideline is intended to assist in the collection of relevant technical information which serves as evidence that the manufacturing process changes will not hurt the quality, safety, and efficacy of the drug product. The document does not prescribe any particular analytical, nonclinical or clinical strategy. The main emphasis of the document is on quality aspects.
Q6A Specifications: Test procedures and acceptance criteria, for new drug substances and new drug products
This guideline is intended to assist to the extent possible, in the establishment of a single set of global specifications for new drug substances and new drug products. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures for new drug substances of synthetic chemical origin, and new drug products produced from them, which have not been registered previously in the United States, the European Union, or Japan.
The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, and process validation, and by specifications applied to them throughout development and manufacture. This guideline addresses specifications. Let those tests, procedures, and acceptance criteria play a major role in assuring the quality of the new drug substance and new drug product at release and during shelf life. Specifications are an important component of quality assurance but are not it only. Component. All of the considerations listed above are necessary to ensure the consistent production of drug substances and drug products of high quality.
This guideline addresses only the marketing approval of new drug products (including combination products) and, where applicable, new drug substances: it does not address drugs. substances or drug products during the clinical research stages of drug development. This guideline may apply to synthetic and semi-synthetic antibiotics and synthetic peptides of low molecular weight; however, it is not sufficient to adequately describe specifications of higher molecular weight peptides and polypeptides and biotechnological/biological products. The ICH Guideline Specifications Test Procedures and Acceptance Criteria for Biotechnological/Biological Products address guideline specifications, tests, and procedures for biotechnological/biological products. Radiopharmaceuticals, products of fermentation, oligonucleotides, herbal products, and crude products of animal or plant origin are similarly not covered.
Guidance is provided about acceptance criteria that should be established for all new drug substances and new drug products. Le universal acceptance criteria, and those that are considered specific to individual drug substances and/or dosage forms. This guideline should not be considered all-encompassing. New analytical technologies, and modifications to existing technology, are continually being developed. Such technologies should be used when justified.
Dosage forms addressed in this guideline include solid oral dosage forms, liquid oral dosage forms, and parenterals (small and large volume). This is not meant to be an all-inclusive list or to limit the number of dosage forms to which this guideline applies. The dosage forms presented serve as models, which may apply to other dosage forms which have not been discussed. The extended application of the concepts in this guideline to other dosage forms, e.g. to inhalation. dosage forms (powders, solutions, etc.), to topical formulations (creams, ointments, gels), and transdermal systems, is encouraged.
Q6B Specifications: Test procedures and acceptance criteria for biotechnological/biological products
The principles adopted and explained in this document apply to proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates). These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be highly purified and characterized using an appropriate set of analytical procedures.
The principles outlined in this document may also apply to other product types such as proteins and polypeptides isolated from tissues and body fluids. To determine applicability, manufacturers should consult with the appropriate regulatory authorities.
This document does not cover antibiotics, synthetic peptides and polypeptides, heparins, vitamins, cell metabolites, DNA products, allergenic extracts, conventional vaccines, cells, whole blood, and cellular blood components. A separate ICH Guideline, “Specifications: Test Procedures and Acceptance Criteria for New Drugs Substances and New Drug Products: Chemical Substances” addresses specifications and other criteria for chemical substances.
This document does not recommend specific test procedures or specific acceptance criteria nor does it apply to the regulation of preclinical and/or clinical research material.
Q7 Good manufacturing practice guide for active pharmaceutical ingredients
This document (Guide) is intended to guide good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess.
In this Guide “manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this Guide, the term “should” indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance. For this Guide, the terms “current good manufacturing practices” and “good manufacturing practices are equivalent.
The Guide as a whole does not cover safety aspects for the personnel engaged in the manufacture, or aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.
This Guide is not intended to define registration/filing requirements or modify pharmacopeia requirements. This Guide does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments registration/filing documents must be met.
Q8 (R2) Pharmaceutical development
This guideline is intended to provide guidance on the contents of section 3.2.P.2 (pharmaceutical development) for drug products as defined in the scope of module 3 of the common technical document (ich guideline m4). The guideline does not apply to the contents of submissions for drug products during the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. This guideline might also be appropriate for other types of products. To determine the applicability of this guideline to a particular type of product, applicants can consult with the appropriate regulatory authorities
Q9 Quality risk management
This guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development. manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging, and labeling materials in drug (medicinal) products, biological and biotechnological products).
Two primary principles of quality risk management are
- The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and
- The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.
Q10 Pharmaceutical quality system
This guideline applies to the systems supporting the development and manufacture of pharmaceutical drug substances (te, API) and drug products, including biotechnology and biological products, throughout the product lifecycle.
The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognizing the differences among, and the different goals of each stage.
For this guideline, the product lifecycle includes the following technical activities for new and existing products:
- Drug substance development;
- Formulation development;
- Manufacture of investigational products;
- Delivery system development;
- Manufacturing process development and scale-up;
- Analytical method development.
- New product transfers during Development through Manufacturing:
- Transfers within or between manufacturing and testing sites for marketed products.
- Acquisition and control of materials;
- Provision of facilities, utilities, and equipment;
- Production (including packaging and labeling);
- Quality control and assurance:
- Distribution (excluding wholesaler activities).
- Retention of documentation;
- Sample retention;
- Continued product assessment and reporting
Q11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities)
It addresses aspects of development and manufacture that pertain to drug substances, including the presence of steps designed to reduce impurities. In addition, ICH Q11 provides further clarification on the principles and concepts described in ICH Guidelines on Pharmaceutical Development (QS). Quality Risk Management (09) and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of the drug substance.
Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management
This guideline provides a framework to facilitate the management of post-approval CMC changes more predictably and efficiently. It is also intended to demonstrate how increased product and process knowledge can contribute to a reduction in the number of regulatory submissions. Effective implementation of the tools and enablers described in this guideline should enhance the industry’s ability to manage many CMC changes effectively under the firm’s Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight before implementation
Q13 Continuous manufacturing of drug substances and drug products
The new ICH guideline will establish harmonized scientific and technical requirements needed to fulfill regulatory expectations for the implementation and assessment of CM to improve access to medicines. An ICH guideline would facilitate international harmonization and could reduce barriers to the adoption of CM technology.
Q14 Analytical procedure development
The new guideline is proposed to harmonize the scientific approaches of Analytical Procedure Development and to provide the principles relating to the description of the Analytical Procedure Development process. This new guideline is intended to improve regulatory communication between industry and regulators and facilitate more efficient, sound scientific, and risk-based approval as well as post-approval change management of analytical procedures.
Harmonization achievements in the quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing, and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.
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