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A harmonized global specification is possible providing that the procedures and acceptance criteria defined are acceptable to regulatory authorities in all regions.
A substance is any matter that may be of human, animal, vegetable (plant) or chemical origin. Substances intended for pharmaceutical purposes are used as active ingredients (drug substances) or excipients (auxiliary substances) for the production of medicinal products. They may be obtained from natural sources, by chemical synthesis or by a fermentation procedure. Recombinant proteins and substances derived by biotechnological processes based on genetic modifications are characterized biotechnological substances.
Human blood, blood products and other substances of animal origin are characterized biological ones. Chemical substances are naturally occurring chemical materials or products obtained by chemical synthesis. As dictated by legislative rules,1 manufacturing and control of chemical materials intended for pharmaceutical purposes are performed using procedures that are designed to ensure a consistent quality and compliance with the requirements of approved specifications. These should be established in accordance with accepted standards and consistent with the manufacturing process of the material.
A specification is a quality standard. It establishes the criteria to which a substance should conform to be considered acceptable for the manufacture of medicinal products. Thus, specification includes a list of tests, references to analytical procedures and appropriate acceptance criteria for the tests described. If the substance meets the acceptance criteria when tested according to the listed analytical procedures, then it conforms to specification. Approved specifications are provided by Pharmacopoeias in each region, such as the United States Pharmacopoeia (USP), Japanese Pharmacopoeia (JP) and the European Pharmacopoeia (EP).2-4 The relevant information is given in individual monographs, but also in general monographs and general chapters.5,6 Excellent technical guidelines have also been published.7-11
Whereas differences in pharmacopoeial specifications among regions usually exist, a harmonized global specification is possible providing that the procedures and acceptance criteria defined are acceptable to regulatory authorities in all regions. Harmonization has already been accomplished in a series of excipient monographs and general chapters. In case there is no available pharmacopoeial monograph, raw material manufacturers must create approved specification and all other scientific data according to the technical guidelines, general monographs and good manufacturing practice (GMP) requirements.
Although the use of biotech derived products has considerably increased in the last two decades, most of the substances still used for pharmaceutical purposes are chemicals. These chemicals, which are either pharmacologically active or excipients, represent discrete moieties, but are sometimes mixtures. The processes followed for the production of these substances are similar. Therefore, their specifications are similar too. Excipients are included in the medicinal product to facilitate manufacture, enhance stability and to contribute to product attributes such as biopharmaceutical profile, appearance and patient acceptability. Depending on the formulation, certain substances may be added either as active ingredients or excipients. Organic solvents and water are often used and they must meet strict quality specifications.
Water for pharmaceutical purposes is the most common chemical component in pharmaceutical production operations. Specific grades such as purified water, water for injections and highly purified water are used at different stages in the production of raw materials, medicinal products and cleaning operations as well. Medicines other than those requiring sterile or apyrogenic water are prepared with purified water. Approved specifications of purified water in bulk are shown in Table I.
Table I Pharmacopoeial specifications of purified water in bulk produced on manufacturing site.
Approximately 5-20 separate tests are selected to be included in the specification of a chemical substance presented in a pharmacopoeial monograph. These tests should address and confirm appearance, identity; physical and functionality-related characteristics; and chemical and microbiological purity. They are carried out routinely during manufacture (in process testing) or at the time of release. Substances having different grades or forms must be tested according to the same individual monograph. However, additional tests should be applied for the qualification of the different grades.
Identification, using specific tests, is the confirmation of a chemical entity. Organic molecules are identified by infrared absorption spectrophotometry (IR). Different procedures, such as liquid chromatography (LC), gas chromatography (GC) and thin layer chromatography (TLC), are also executed. However, the use of at least two different procedures based on a different principle is generally acceptable. If the organic molecule is a salt, specific ion identification testing is necessary.
Identification tests based on the measurement of the melting point temperature, freezing point temperature, kinematic viscosity, angle of optical rotation, refractive index and relative density of liquids are frequently applied. Inorganic molecules are identified through the characteristic chemical reactions of their ions. Some EP monographs under the title "Identification" contain the subdivisions "First Identification" and "Second Identification." The test or tests that constitute the "Second Identification" may only be used if the substance is fully traceable to a batch certified to comply with all the requirements of the monograph, whereas those that constitute the "First Identification" can be used in all cases.
Polymorphism. Polymorphism is the property of a chemical substance to exist in different crystalline forms. Common methods to determine the existence of multiple forms are X-ray diffraction, IR, nuclear magnetic resonance, scanning electron microscopy and thermal analysis. Polymorphism is an important factor mainly for drug substances.
Purity. Chemical purity is generally ensured by testing for related substances, residual organic solvents, heavy metals and by the quantitative determination of the content (assay). More specific chemical tests, which ensure a better quality characterization of the sample, are mandatory in certain cases.
Control on related substances (related compounds) is very significant mainly for organic drug substances. Impurity profiles are better decided by a gas or liquid chromatographic procedure. High performance liquid chromatography (HPLC) is the best analytical method for this purpose. Baseline separation of all the potential organic impurities (impurities arising during the chemical synthesis and degradation products) should be performed. EP monographs report the acceptance criteria for organic impurities in terms of peak area with an indication of the corresponding nominal concentration. Special information and recommendations for interpreting the test for the related substances is also provided in the general chapter concerning this topic.6
Organic solvents are used in the production of pharmaceutical substances and medicinal products. These solvents, although volatile, are not completely removed by practical manufacturing and subsequent purification procedures. Residues should be limited to the levels approved by the international Conference on Harmonization (ICH).10 There are three classifications of solvents, which are graded according to their toxicity. Solvents that should be avoided are Class I. Class II solvents should be of limited use, whilst Class III solvents are those with the least toxicity and can be routinely used. Control of the residual solvents is regularly performed by GC with headspace injection. The non-specific test for loss of drying may be applied when only Class III solvents are used in the production process. Periodic or skip testing at release can be applied, but batches that have not been tested for residual solvents must still meet acceptance criteria.
Heavy metals. Heavy metal testing demonstrates that the level of metallic impurities coloured by the sulfide anion does not exceed the limit specified in the individual monograph regarding parts per million of lead in the substance under examination. Concomitant visual comparison with a control prepared from a standard lead solution is performed in this limit test. Metallic cations, except lead, that typically respond are mercury, cadmium, silver, antimony, bismuth, tin and copper. Quantitative determination of metallic compounds in pharmaceuticals, when necessary, is performed by atomic absorption spectrometry (AAS). An estimation of total inorganic impurities can also be done by determining the residue of ignition or the sulfated ash of the sample.
Suitable methods must be applied for the quantitative determination of the pharmaceutical substances. HPLC or GC are proposed as the most specific methods for determining the content of a pharmaceutical substance. In many cases, the same stability-indicating procedure for both assay and the quantitation of impurities is employed. In cases where a non-specific analytical procedure (for example, a volumetric titration) is adopted for the assay, other supporting analytical procedures are simultaneously proposed (for example, HPLC determination of the related substances) to achieve overall specifity. Assay results are expressed with reference to the anhydrous or to the dried substance, thus water content or loss on drying tests must be conducted.
Water content.Water content determination is very important when the substance is known to be hygroscopic or a stoichiometric hydrate. Karl Fischer titration is the most widely known specific procedure for water content estimation, but sometimes the non-specific loss on drying test is considered adequate.
Microbiological. The microbiological quality of pharmaceutical substances is adequately controlled by performing tests for total viable aerobic count (TVAC) for specified micro-organisms and for sterility — the latter test is performed if the substance is intended for the preparation of sterile dosage forms or if offered as sterile grade. Pyrogen testing or a bacterial endotoxins test should be applied in endotoxin-free grade substances. The type of microbial testing should be based on the nature of the substance, method of manufacture and the intended use. A decision tree that gives further guidance is published in the ICH guideline.8
Functionality. Physical and other functionality-related characteristics are different between different grades of the same chemical entity. Such characteristics include
Differentiation between different qualities of the same chemical entity is referred to as qualification. Near IR absorption spectrophotometry (NIR) is perhaps the most useful analytical technique for the qualification of chemical substances. NIR can also be used for identification.
Particle size distribution is conducted by laser diffraction or analytical sieving. Appropriate methods for testing intrinsic dissolution rate, bulk and tapped densities, true density, specific surface area and flowability are described in the pharmacopoeias. Control of these parameters affords an important tool in the characterization of bulk active substances and excipients.
Quality specifications of substances for pharmaceutical use are a very important issue, having a significant impact on medicines. These specifications must be presented in detail on the certificate of analysis (CoA) of the raw material along with reference to the latest pharmacopoeial individual monograph, if it is provided. This is mandatory for both raw material manufacturers and the end-users of pharmaceutical substances.
Raw materials manufacturers must routinely test the pharmaceutical substances they produce according to pharmacopoeial instructions. They usually test their products according to all major pharmacopoeias, if harmonized specifications do not exist, to ensure global acceptance. Periodic control (skip testing) of some parameters is allowed only if it is applied by a fully validated manufacturing procedure.
End-users initially evaluate their raw material suppliers by carrying out full testing on the first lots of the purchased products; afterwards they only routinely carry out identification testing, accepting the CoA of their suppliers or they perform full testing only on selected batches according to a written standard operating procedure (SOP).
However, since transport and storage can cause changes that are beyond initial control of the manufacturers, it is better that the materials are further examined by the end-users before use. In either case, QA/QC managers and other personnel involved in testing, the preparation of CoAs and relevant SOP writing must be completely informed and familiar with the afore mentioned topic. The issued CoAs will then be in full compliance with pharmacopoeial and GMP requirements.
Information on the specifications of the drug substance and the excipients that formulate the medicinal product must also be included in module 3 of the common technical document (CTD), which is the new format required for all marketing authorization applications. Therefore, personnel involved in the preparation of these documents and regulatory affairs personnel should be similarly informed. Finally, the same applies to personnel who deal with formulation, production, analytical development, and those responsible for the selection of the raw materials.
Pharmacopoeial monographs, chapters and technical guidelines are regularly revised and updated because of continuous changes in technology and subsequent regulatory demands. Personnel from all sectors of the pharmaceutical industry must be aware of these updates to keep up with the ever changing requirements in the industry.
2. USP 27-NF 22 (US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, Maryland, 20852, USA, 2003).
4. European Pharmacopoeia, 5th Edition (EDQM, 226 avenue de Colmar BP 907, F-67029 Strasbourg, France, 2004).
5. "Substances for Pharmaceutical Use," Monograph Nr 01/2005:2043, European Pharmacopoeia, 5th Edition (EDQM, 226 avenue de Colmar BP 907, F-67029 Strasbourg, France, 2004) p 586.
6. "Control of Impurities in Substances for Pharmaceutical use," Monograph Nr 01/2005:51000, European Pharmacopoeia, 5th Edition (EDQM, 226 avenue de Colmar BP 907, F-67029 Strasbourg, France, 2004) p 559.
7. Good Manufacturing Practices for Bulk Pharmaceutical Excipients, International Pharmaceutical Excipients Council's (IPEC) Revised Guidelines (2001), Pharmeuropa 14(2), 223 (2002).
8. Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, ICH Harmonized Tripartite Guideline QA6, www.ich.org
9. Impurities in New Drug Substances, ICH Tripartite Harmonized Guideline, Q3A(R), www.ich.org
10. Impurities: Guideline for Residual Solvents, ICH Harmonized Tripartite Guideline Q3C, www.ich.org
11. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, ICH Tripartite Harmonized Guideline, QA7, www.ich.org
Nikolaos Grekas is a senior scientist at ELPEN A.E. Pharmaceutical Co. Inc., 95 Marathonos Ave., 19009, Pikermi, Attica, Greece. Tel. +302 1 0603 9326, Fax +302 1 0603 9300. firstname.lastname@example.org