In this third article in the series on the drug development process, details are given of aspects of pharmaceutical development. These form the “quality” aspects of the quality, safety, and efficacy criteria that have to be met in the development of a new pharmaceutical product
The first article in this series gave an overview of the drug development process.1 The second described the options available in the United Kingdom and the rest of Europe for successful registration of pharmaceutical products to allow marketing in member states of the European Union (EU).2 This and subsequent articles will cover the different stages of the development process.
Scientific assessment and achievement of quality, safety, and efficacy form the three main criteria that any company wishing to place a medicinal product on the market must satisfy. The registration procedure utilises the considerable scientific knowledge that pharmacy undergraduates are uniquely taught.
Quality issues cover all aspects of the chemical, pharmaceutical, and biological development of a new product. They are covered in Part II of the marketing authorisation application (MAA).1 In essence, this covers the following for ingredients and finished products:
Coverage of these elements of pharmaceutical development is essential for all products for human or veterinary use, including chemically active substances, radiopharmaceutical products, biological medicinal products, or vegetable medicinal products. Some variation does occur, however, in the requirements for specific members of these groups.
In order to assist applicants in the European Community (EC) to provide the necessary information for each of the above topics, guidelines or “Notes for guidance” have been produced by the EC Committee for Proprietary Medicinal Products (CPMP) and Committee for Veterinary Medicinal Products (CVMP) of the European Agency for the Evaluation of Medicinal Products (EMEA). Although they have no legislative standing, applicants must justify their own processes where they differ from those given in the published guidelines. Adopted and draft EC “quality” guidelines are listed in Table 1. Those that are currently under development within the International Conference on Harmonisation of the technical requirements for the registration of human medicinal products (ICH) and which are, therefore, also to be adopted within the EC, are listed in Table 2.
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The guidelines on quality aspects of the MAA are published as a compendium in Volume 3A of the “Rules governing medicinal products in the European Union”.3 The following summary of quality requirements is based upon the guidelines published in this volume. (The numbering of EC guidelines is convoluted and inconsistent. Later documents, or earlier ones which have been the subject of revision, are numbered as in Tables 1 and 2; earlier ones still can only be referenced by their original EC designation. The designation in Volume 3A of the “Rules” is given in the discussion below.)
Guideline III/847/87 reflects the need for pharmaceutical development studies to be carried out to ensure that the dosage form and formulation of a proposed medicinal product are appropriate. Batch reproducibility is also critically ensured by compliance with the guideline.
Development pharmaceutics — constituents Constituents comprise the active substances and excipients. The active substance must be shown to be compatible with the excipients, and the effect of any variation in physical characteristics (eg, particle size) on the formulation must be studied. If there is a risk that any change in physical characteristics may produce changes in bioavailability or any other actions of the formulation, the controls put in place to monitor this must be described. The presence of any overage produced during manufacturing must be justified.
The role of all excipients must be explained. If an unusual excipient is used, in order to produce a particular effect in the formulation, full information on the excipient must be given.
Composition The requirements vary according to the type of dosage form. For liquid dosage forms, the effect of changes in physical characteristics must be demonstrated. The effect of changes in pH on the active ingredient must be shown. Other factors (eg, ease of dissolution, and changes in aggregation) must also be considered. The inclusion of other non-excipient additives (eg, preservatives and antioxidants) must also be justified. If a product is to be given intravenously, compatibility with other products is of particular importance. For semi-solid dosage forms, similar considerations regarding pH and additives must be addressed.
Dissolution of a solid dosage form is critical, and the tests should be carried out for both non-modified release and modified-release (eg, prolonged release) formulations. Correlation of in vitro with in vivo studies may be required for certain formulations.
It is essential that the mixture of active ingredient and excipients in a solid dosage form is uniform. Although the European Pharmacopoeia (PhEur) refers to single-dosage forms containing 2mg per dose or less, the guideline states that homogeneity must be ensured for all solid dosage forms.
Container and closure Any possible interaction between the container and closure and the formulated product must be documented. This can include the extraction from solution of one or more of the ingredients, which is especially problematic with glass and rubber container and closure materials. Possible leaching of ingredients must also be considered. If a dosing device is to be used, evidence must be presented that the dose received by the patient is reproducible.
Process validation The concept of process validation deals with the manufacturing process and its quality. It is associated with good manufacturing practice (GMP). It is, however, more concerned with non-standard methods of manufacturing that might be used in the production process, and ensuring that they produce a final product of expected quality
Guideline III/3421/93 covers the marketing authorisation application and good manufacturing practice, the manufacturing formula, the description of the manufacturing process, the description of the manufacturing chain, the validation of the manufacturing process, and special items.
GMP is defined in EC directive 91/356/EEC, and all medicinal products must be manufactured according to GMP. The MAA should contain information specific to the medicinal product under review, and general aspects of GMP need not be described. This guideline describes those elements of GMP that should be described.
Manufacturing formula The product must be manufactured to a formula. This includes information about the batch size and any variations which might be allowed in the finished product batch size, the basic ingredients of the product (including their specifications and any overages which are allowed), and the variation in quantity (if any) which the formula permits in the use of individual ingredients (these must be specified for both active ingredients and excipients).
Description of the manufacturing process A description of the manufacturing process must be given, together with any variations which might be allowed in exceptional circumstances. The description should include the equipment used and the in-process controls which have been built into the manufacturing process. A flow-chart of the process is essential, although the level of detail should not be so specific as to be restrictive upon the manufacturer in making minor alterations. No major changes to the manufacturing process can be permitted unless previously agreed with the regulatory authority that issues the marketing authorisation. What is important is that the process produces a medicinal product of expected and known specification.
Description of the manufacturing chain All sites where manufacturing and assembly of the product takes place must be notified, even if all the sites belong to the same company. The name of the company responsible for final batch release must also be given.
Validation data of the manufacturing process Process validation must be described if there are any doubts about the ability of the manufacturing process to guarantee the specifications of the finished product.
Special items A range of “special items” are included in the guideline to cover unusual manufacturing issues that might arise. These include any method of sterilisation used, the reprocessing of any leftover manufactured product, the removal of solvents or gases, the cleaning and sterilisation of primary packaging material, and details of production areas.
The high potential carcinogenic effect of ethylene oxide has led to the recommendation in guideline III/9261/90 that the compound should be used only when it is pharmaceutically essential to do so, and only when a limit of 1ppm is applied.
Categories of the use of ethylene oxide Ethylene oxide is a surface-only sterilising agent.
Although it can be used in with pharmaceutical raw materials, finished products, and containers, its use on each occasion must be justified.
Specifications and test procedures Specifications and test procedures cover the use of ethylene oxide on raw materials, the finished product, and containers.
The need for microbial decontamination and sterilisation (eg, of starting materials, packaging materials and finished products) in the manufacture of medicinal products may require the use of ionising radiation.
Additional information to that given in guideline III/9109/90 on the use of ionising radiation is found in an annex within volume 4 of the “Rules governing medicinal products in the European Union”.4
Administrative data Full details of the product to be irradiated are required and the stage of the manufacturing process the material is at (eg, whether it is a starting material or a finished product). Batch size data are also required.
The purpose of the irradiation must be given, with the minimum dose to achieve this and the maximum permissible dose that can be used. The manufacturer’s details must also be given and the location of the sites where irradiation is carried out.
Manufacturing process Descriptions of the irradiation plant and process must be given. Full details of the passage of the product through the irradiation process are required (eg, the dimensions and material of the irradiation container, and the loading pattern of the container within the irradiation unit).
Validation of the irradiation procedure Validation details must relate to the procedure and dose, the purpose of the irradiation, and the quality of the product. This must include information on whether the irradiation is for reduction of a bioburden or for sterilisation purposes, and that the irradiation has produced the desired effects. It must be stated if there are any qualitative or quantitative changes to the product as a result of the irradiation and, if there are, whether these have any significance. It needs to be determined whether the changes have affected the quality of the product, or the potential health and safety of the patient who will use the product?
The safety of the irradiated product for the patient is an issue that should be addressed in the quality expert report.
Guideline III/478/87 is intended for use by manufacturers who have produced a new active substance that is not the subject of a monograph in either the European Pharmacopoeia or a pharmacopoeia of one or more of the 15 member states.
Identity of the material Full details must be given of the name of the product, plus a description of the material, including its physical form and molecular formula. Its appearance should also be described.
Manufacture The guideline states that “a concise but comprehensive account of the manufacture of the active substance should be provided”. This includes information about the manufacturing process, a description of the process, and details about quality control during synthesis.
Again, the use of flow charts to illustrate the synthetic process is recommended. All the ingredients used in the synthesis must be described and their quality detailed (eg, whether they are of pharmacopoeial standard). The controls apply to starting materials and must also indicate the presence of any impurities introduced during the synthetic process. All quality control checks that are carried out at intermediate stages of the process must also be described.
Development chemistry The structure and chemical and physicochemical properties of the new substance must be described. Considerable importance is attached to being able to characterise fully the chemical structure of the substance, and all the methods used to do so must be fully explained. Again, this information is often required to be supported by the expert in the quality expert report. The latest techniques should be used at all times, ensuring that the data provided are as accurate and clear as possible.
The physicochemical characteristics must be fully described. These include the material’s solubility in a variety of solvents, the presence or absence of polymorphism, and its pKa and pH values.
Regulators are always keen to be made aware of any unusual aspects associated with the compound during analytical development. The precision and accuracy of the tests must be described, and any variation in the results, which is especially likely in substances of biological origin, must be detailed.
Impurities The greater the number of ingredients used in the synthetic processes, the greater the risk of the presence of impurities in the finished product. Impurities can arise from the synthesis itself, from the use of solvents and other materials during purification processes, and the inevitable presence of degradation products should the active substance be shown to be relatively unstable.
The test procedures used to detect and identify potential impurities must be listed, together with the limits imposed on their presence. A summary of the test results on impurities in batch samples is also required.
Active substance specification Tests should be carried out to define the specification for the active substance in terms of its physical characteristics, its identity, its purity and limitation of impurities, and its potency. All analytical methods should be described in detail.
Batch analysis It is vital that the results from routine quality control of the active substance should be presented. Ideally, these results should be from samples which are to be or are being used in clinical trials and in toxicity tests. The results should include the date of manufacture, the batch size and number, the place of manufacture, the results of analytical tests, and the intended use of the batches.
Reference standards The use of any reference substances for the analytical process should be described.
Radiolabelled product If the new active substance is a radioactive isotope, all of the above requirements apply.
Active substances may be classified as new active substances, as existing active substances not included in the PhEur or the pharmacopoeia of a members state, or as an active substance that is included in the PhEur or the pharmacopoeia of a member state.
New active substances The requirements for new active substances are defined above in the guideline III/478/87, “Chemistry of active substances”. Information on the new active substance may be supplied by the applicant company or, if it is manufactured by a third party, using the European Drug Master File (DMF) procedure. (For an explanation of the DMF procedure, see below.)
Existing active substances not included in the PhEur or the pharmacopoeia of a member state The data requirements are the same as that for new active substances, with data supplied either directly by the applicant company or via the DMF procedure.
Pharmacopoeial active substances Pharmacopoeial active substances include inorganic substances, vegetable substances and vegetable substance preparations, materials derived from biotechnology processes, organic substances that are extracted from animal or human material, or organic substances that are manufactured or extracted.
Evidence of the suitability of the pharmacopoeial monograph is required in each case. Control of the levels of impurities allowed in the monograph must be justified, and the ways in which the material is prepared must be critically justified by the applicant. The suitability of the monograph must be shown by the applicant to the regulatory authority. A decision tree outlining the selection of the appropriate regulatory procedure for active substances is included in the guideline.
Guideline III/5370/93 covers both the legal basis for the DMF procedure, and the working of the procedure itself. The procedure can be applied to both human and veterinary medicinal products.
The legal framework for the DMF procedure is based upon the annex to directive 75/318/EEC (as amended), and directive 81/852/EEC “Control of starting materials” (as amended). It applies to active substances not included in the PhEur or in the pharmacopoeia of a member state and to pharmacopoeial active substances.
In the latter case, the monograph is deemed inadequate to control the quality of the active substance when it is manufactured by a third party. In this case, a detailed description of the manufacturing method, quality control procedures, and process validation must be supplied direct to the regulatory authority by the third party manufacturer.
However, sufficient information about these processes must be given by the third party to the applicant company to allow the applicant company to take full responsibility for the manufactured medicinal product as marketing authorisation holder.
The DMF procedure applies to all classes of substances described in the previous guideline. It is the responsibility of the applicant company to ensure that all the information required by the regulatory authority is in fact supplied in the DMF.
Content of the DMF The content of the DMF is divided into that supplied by the applicant company and that supplied by the active substance manufacturer (ASM). However, the ASM must supply the applicant company with sufficient information about the active substance specification for the latter to be able to take responsibility for the material in the approved authorisation.
The ASM provides the applicant’s part of a DMF to the applicant directly and it becomes part of the MAA. The ASM restricted part is submitted to the regulatory authority alongside the applicant’s part.
Information accompanying a DMF A “Letter of access” supplied by the ASM must accompany the DMF to permit the regulatory authority to assess the data in the DMF on behalf of the applicant company. The ASM must also agree to inform the applicant company and the authorities if there are any significant changes to the specification of the active substance which is the subject of the DMF.
Critical appraisal of the DMF documentation The ASM restricted part of the DMF must contain a critical appraisal (validation) of the manufacturing method, batch analysis, and specification and routine tests which have been applied.
Glossary of terms A brief glossary is included in the guideline.
Use of the DMF procedure A question and answer guide to the implementation of the DMF procedure is also included in the guideline. This is intended for use by the chemical industry (the primary manufacturer of active substances) and the pharmaceutical industry (the main suppliers of formulations for MAAs).
Guideline III/5442/95 applies only to active substances prepared by chemical synthesis. It does not apply to certain other products, including those generated by biotechnological processes, radiopharmaceuticals, herbal products, and products of animal or plant origin.
Classification of impurities Organic impurities can arise during the manufacturing process and storage of the chemical, and can include materials used or produced at any stage of the manufacturing process (eg, starting materials, by-products, reagents, ligands, and catalysts). Inorganic impurities also derive from the manufacturing process and can include heavy metals, inorganic salts, and filter aids. Residual solvents tend to be well-established materials with known toxicity, and their impurities are usually well characterised.
Rationale for the reporting and control of impurities The section on the rationale for the reporting and control of impurities outlines the information that should be provided by the applicant company about impurities that might arise during synthesis, purification, and storage. It should describe those impurities that would be expected from the materials being used, plus the tests that have been carried out to demonstrate their presence or absence, and if present, the limits and quantities applied to those impurities. All impurities present at a level of 0.1 per cent or more must be identified; the same applies to degradation products identified in stability studies at recommended storage conditions.
Pharmacopoeial procedures are often used to detect and quantify inorganic impurities. Limits on the presence of such impurities should similarly be based on pharmacopoeial data. The same criteria apply to the quantification and identification of residual solvents.
Analytical procedures All analytical procedures for the detection of impurities must be validated and proven suitable for their purpose. Any variation between analytical procedures used during pharmaceutical development and during the commercial manufacture of the product must be explained and justified.
Reporting impurity content of batches A batch of a medicinal product may be used (among others) for clinical studies, for assessment of toxicological data, and for stability testing. Tabulated data covering impurities in specific batches must be presented. The data should include the batch identity and size, the date and site of manufacture, the manufacturing process used, the individual and total impurity content, the intended use of the batches, and the analytical procedure used to detect the impurities.
Specification limits for impurities The specification for the new substance should include data on identified and unidentified impurities found during the commercial manufacturing process. Reasons for the inclusion or exclusion of impurities from the specification must be given. This should take into consideration the likely effects — harmful or otherwise — of the impurity.
Qualification of impurities Qualification is the process of acquiring and evaluating data which establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. As above, reasons for selecting particular impurities for qualification must be based on safety considerations. When safety or clinical studies or both have been carried out, the level of any impurity is considered “qualified”. A decision tree is appended to the guideline to determine the action to be taken should the threshold limits for impurities be exceeded. The threshold limits are based upon the maximum daily dose, defined as either less than or equal to, or more than, an intake of 2g of substance per day.
New impurities Any change in the manufacturing process may lead to the generation of a completely new, previously absent, impurity. Again, any decision about the identification and detection of the new impurity must be based upon safety considerations.
Glossary A short glossary explains the terms used in the guideline.
Data about the excipients in the formulation must be developed in a similar way to that for the active substance. Guideline III/3196/91 refers to specific parts of volume 2 of the “Rules governing medicinal products in the European Union,5 which details data requirements for the active substance. The guideline makes clear that data in these sections relating to the requirements for active substances must be applied to excipients.
Composition of the medicinal product Full details of the excipients in the formulation must be given, including their common name, the amount in which they are being used, and the standard of the material being used. Mixtures of excipients must be qualitatively and quantitatively described.
Development pharmaceutics An explanation of the reasons for the choice of an individual excipient, and standard of material chosen, must be given.
Excipients An annex to the guideline describes examples of different kinds of excipients. The specifications and routine tests applied to an excipient follow the same pattern as for active substances. The specification again depends upon the presence of the material in the PhEur or a pharmacopoeia of a member state, and the scientific data required about the excipient must justify the choice and use of a particular excipient.
If the excipient is well known and has been used in medicinal product formulations for a long time, the properties and characteristics will be clearly defined and the level of scientific data required is correspondingly diminished.
If, however, the excipient is new, it should, in effect, be treated in the same way as a new active substance, and the data requirements are the same (ie, a new MAA is, in effect, required for the excipient).
The finished product It is not usually a requirement to carry out identity testing and assays of the excipients in a finished product, if all the earlier requirements have been fulfilled.
Guideline III/90/90 covers only those plastic packaging materials that come into direct contact with the medicinal product (eg, the packaging material of a blister pack that surrounds a tablet). The discussion below refers to the container as the packaging material, although it equally applies to the closure and other parts of the container.
Immediate packaging A full description must be given of all aspects of the container used as the immediate packaging. Details must include the method of opening, aspects of the design that make the container a multidose one, and measures taken to ensure that the container is both tamper- and child-resistant.
Development pharmaceutics It will already have been determined what the method of administration, the stability of the product, and any method of sterilisation is to be. Reasons for the choice of the container in relation to these issues must be fully given.
Packaging material A detailed summary is provided in the guideline of the importance of fully characterising the plastic used in the packaging material. It must include details of the technical characteristics of the plastic and any additives in the finished plastic. The plastic’s manufacturer must also be given.
Stability aspects It is fully recognised by the guideline that plastic materials are inherently unstable and that leaching of ingredients can occur both from the finished product into the plastic and from the plastic into the pharmaceutical dosage form. The stability of the finished product in contact with the plastic, particularly if it is not a solid dosage form, must be fully characterised.
Guideline III/3324/89 summarises specifications and test procedures, and briefly refers to batch analysis. Appended is a glossary of terms used in the guideline.
Specifications This guideline is important in that it lists the “quality” aspects of a medicinal product. Quality characteristics cover the following areas:
Other issues addressed include the relationship between the specifications referred to in the MAA and those of a pharmacopoeia and, in particular, the PhEur, the relationship between the specifications on manufacture (batch release) and at the end of the agreed shelf-life, and the specifications and routine tests used for the batch release of the finished product upon manufacture. Acceptance limits for the specifications are also described.
Test procedures Reproducibility of data on the medicinal product’s specification is very important. Not only should the manufacturer be able to reproduce the data in a reliable way, official laboratories should be able to do so up to the end of the shelf-life of the product. If applicable, a pharmacopoeial method of analysis can be used. If this does not exist, alternative methods of analysis must be validated against an official pharmacopoeial method.
Batch analysis Batch analysis must include the results for all specifications at release, from all sites at which manufacture has taken place.
As previously, this guideline on impurities applies to only to chemically synthesised active ingredients. It defines guidance on the content and determination of impurities in a new medicinal product. These are referred to as degradation products. It is, in effect, an annex to the guideline on “Impurities in new active substances” (see above). It applies only to the impurities from the active ingredient(s). It does not apply to excipients, or to impurities which might exist in the product during development.
Analytical procedures The MAA should include data to demonstrate that the analytical procedures used are suitable for the detection and quantification of degradation products in the finished product. If the analytical procedures used during development are different from those used in commercial manufacture of the medicinal product, the differences should be described and justified.
Rationale for the reporting and control of impurities Degradation products identified during stability studies conducted at recommended storage conditions should be summarised. If it is not possible to identify a particular degradation product, the data accumulated during the attempt at identification should be included.
Reporting impurity content of batches The data supplied to show the impurity profile identified in the batch testing of the product is an important indicator of the quality of the manufacturing process and for determining the expiry date for the product. If impurities are revealed from the testing, their possible origin should be discussed (eg, by reference to the date and site of manufacture, the batch number, and the storage conditions).
Specification limits for impurities Limits for expected degradation products under defined storage conditions should be specified. The specification should include the limits for each stated degradation product and the limits for the total degradation products.
“Qualification” of impurities As already mentioned, “qualification” is the process of acquiring and evaluating data which establish the biological safety of an individual impurity or a given impurity profile at specified levels. Reference to the decision tree for safety studies (mentioned in the above guideline) should also be made.
New impurities The degradation profile of a medicinal product may change during pharmaceutical development. If this happens, new degradation products may need to be quantified and identified.
Glossary A glossary of terms used in the guideline is appended to it.
The discussion of the quality guidelines which must be used in the development of a new medicinal product will continue in the next article in this series.
Robin J. Harman is a freelance pharmaceutical and regulatory consultant based in Farnham, Surrey