Compendial standards and the pharmacopoeias
The pharmacopoeias, or compendia, are public collections of standards and tests for the identity, strength, quality, purity and potency of medicines. In the United States the law draws its standards of drug quality and adulteration from them, and manufacturers, regulators and generic sponsors rely on their tests.
What a compendium is
Historically, pharmacists have attempted to ensure that medicines are correctly named and uniformly prepared with acceptable quality, so that patients receive both the medicine the physician prescribed and the correct dose. The writings now called pharmacopoeias or compendia, whether termed dispensatoria, enchiridia, concordiae, receptarii, antidotaria or medicamentaria, were designed to memorialise authentic recipes for named products and to ensure the identity and equivalence of preparations.
The first national US pharmacopoeia, the Pharmacopoeia of the United States of America (USP) of 1820, explicitly stated requirements for naming and identity. It gave a pharmacopoeia the purpose of selecting, from among substances with medicinal power, those whose utility is most fully established and best understood, of forming from them preparations in which their powers may be exerted to the greatest advantage, and of distinguishing these articles by convenient and definite names that may prevent trouble or uncertainty between physicians and apothecaries.
Recipes for making drugs and textbooks for pharmacists were both historical uses of the compendia, but neither is a function of the modern compendia. The compendia are not historical artefacts or old medical books but are updated and used regularly.
USP–NF
USP is a nongovernmental, nonprofit, standards-setting organisation founded in 1820. Its mission is to improve the health of people around the world through public standards and related programmes that help ensure the quality, safety and benefit of medicines and foods. During the 19th century, USP was updated at approximately ten-year intervals by volunteers who met as the US Pharmacopeial Convention, which was formally incorporated in 1900 and is a 501(c)(3) nonprofit organisation working in the public interest. In 1975 the Convention acquired the National Formulary (NF), and it has since published the two compendia in a combined volume, USP–NF. USP has its headquarters in Rockville, Maryland, laboratories in Hyderabad, India, Shanghai, China, and São Paulo, Brazil, and a non-laboratory site in Basel, Switzerland.
USP–NF comprises general chapters about pharmaceutical analysis and monographs, which set tests for the identity, strength, quality and purity of drug substances and drug products, such as Acetaminophen and Acetaminophen Oral Solution. Dissolution is general chapter <711>, and chromatography is given both as general chapter <601> and as <621>. USP 36–NF 31 contained 260 general chapters and nearly 5,000 monographs. NF includes excipients used in pharmaceutical manufacturing, and USP includes drug substances.
Innovator companies tend to submit new monograph proposals to USP shortly before their product's patent expires.
Compendial standards in US law
In the United States, compendial requirements for naming and identity were enacted in law as early as the 1848 Drug Import Act, and more extensively in the 1906 Food and Drugs Act. The 1906 act established the Food and Drug Administration (FDA) and defined drugs as all medicines and preparations recognised in the United States Pharmacopoeia or the National Formulary. It also introduced the concept of adulteration: drugs that differed from the standard of strength, quality or purity in USP or NF were deemed adulterated, that is, contaminated by impurities, and thus unfit for human consumption.
The first USP was published in 1820, but the FDA, the government agency charged with enforcing drug standards, was established in 1906 with a remit to enforce USP and NF standards, and this is in part why USP–NF is nongovernmental. Neither the US federal government nor the FDA publishes the compendia.
In 1937 patients died after taking a sulfanilamide preparation. One account gives 105 deaths and says the sulfanilamide had been formulated with toxic ethylene glycol. Another names the solvent as diethylene glycol and attributes at least 100 deaths to Elixir Sulfanilamide.
The following year Congress passed the Food, Drug, and Cosmetic Act (FDCA), whose section 201(b) deems a drug adulterated if it purports to be or is represented as a drug whose name is recognised in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in that compendium. The determination of strength, quality or purity is to be made in accordance with the tests or methods of assay the compendium sets forth.
Title 21 of the Code of Federal Regulations refers to compendial standards of identity, strength, quality, purity and potency for drug substances, drug ingredients and drug products, for example in §601.12(a)(2) and §514.8(1)(2)(i). Failure to meet these standards is a violation of current Good Manufacturing Practices.
What compendial tests are used for
Manufacturers, purchasers and regulators rely on compendial tests to ensure that items in fact comply with their label claims. Pharmaceutical companies routinely rely on them to ensure the quality of their raw materials, and once a finished product passes compendial tests it can be released into commerce with assurance to manufacturers, regulators and consumers that it is authentic. Compendial tests are also useful because they can be used in many locations and are independent of either a manufacturer's or the US government's participation.
An important use of compendial standards is testing, with reference standards, for identity and other quality attributes. The USP reference standards used in compendial testing are highly characterised specimens of drug substances, excipients (ingredients such as bulking or processing agents), impurities, degradation products, reagents or calibrators. Besides routine batch release testing, they are used to test for counterfeit or substandard medicines, such as antimalarial, antibiotic and anti-HIV drugs around the world.
Items that fail compendial tests may have been adulterated accidentally, as in the sulfanilamide tragedy of 1937, or deliberately for economic gain, as in the heparin and melamine scandals. Compendial monographs are increasingly useful in helping to detect, and in one author's hope to deter, economically motivated adulteration, both in developing nations, as with antimalarial drugs, and in developed countries, as with heparin and melamine.
Generic drugs are approved for marketing in the United States after sponsors demonstrate the equivalence of a generic to an innovator product through an approved Abbreviated New Drug Application (ANDA) (21 CFR 320.21). Generic drug manufacturers rely on compendial monographs and the tests in general chapters when they prepare their ANDAs. The equivalence of generic drugs to innovator products can be assessed with compendial tests and with the ingredient and product monographs in the compendia.
Establishing and maintaining the identity of drug substances and drug products is important from preclinical discovery through clinical trials and into public distribution in global markets. These processes involve scale-up and manufacturing at multiple sites around the world, and compendial tests such as dissolution and chromatography are important tools that help ensure the identity, strength, quality, purity and potency of pharmaceutical ingredients and products.
Compendial science
Broadly, compendial science is the set of skills required to create, apply, and revise or update the compendia. No standard definition is available, but compendial science can be described as the application of chemical and biochemical analytical sciences to medicines within the regulatory frameworks used to ensure the quality of medicinal products delivered to patients. Those regulatory frameworks can be described as a web of standards, regulations and guidances relating to pharmaceutical products, such as the pharmacopoeias, FDA guidances, Code of Federal Regulations requirements, and standards and guidelines from the International Organization for Standardization, the International Conference on Harmonization, the American Society for Testing and Materials and the American National Standards Institute, together with the science that supports the choice of acceptance criteria.
The compendial scientists who use, develop or revise the general chapters and monographs of USP–NF are often analytical chemists, but biomedical writers do not require that level of knowledge. Writers should instead be aware of the compendia as authoritative sources of drug substance and drug product names, and of tests that ensure the identity, strength, quality, purity and potency of innovator and generic medicines in domestic and international commerce.
Quality assurance and protection from fraud both involve the compendia, and they should be well known to biomedical writers, who may be called on to explain concepts related to the identity and quality of pharmaceuticals. It would also help writers to know how the purity of drugs is ensured and how public health officials globally use compendial tests for adulterated and substandard products. Writers who discuss generic drugs and bioequivalence benefit from a firm understanding of the compendia and compendial science. They should also understand the processes by which generic drugs are developed and how their equivalence to innovator products is assessed.
In one author's judgement, it seems worthwhile to expand the education of biomedical writers so that they better understand the importance and applications of compendial tests in ensuring that medicines are correctly named and uniformly prepared with acceptable quality. Compendial science may improve writers' understanding of public standards and their role in ensuring the quality of pharmaceuticals, and thereby their ability to communicate such information.
What medical writers know about the compendia
Biomedical writers generally know about the FDA's activities, but the contents and uses of the compendia are less well known.
From 16 to 30 April 2012, a nine-question survey on familiarity with the compendia went to the 2,453 subscribers of an editing and writing e-mail list hosted by the American Medical Writers Association (AMWA), and 66 members responded, an absolute response rate of 3%. The response did not achieve statistical significance, which at a 95% confidence interval would have required 333 responses, and this limits the inferences that can be drawn. Of the respondents, 52% worked in non-regulatory writing, 29% were regulatory writers and 19% worked in both. The questions on what a compendium is and on what USP–NF contains allowed more than one answer, so their totals do not sum to 100%.
Asked what a compendium is, 82% correctly identified USP–NF as compendia and 65% associated the compendia with drug standards. Only 47% associated them with tests for authentic drugs, even though these are important applications of modern compendia. Of the respondents, 26% thought the compendia contained recipes for making drugs, 24% that they were textbooks for pharmacists, and 12% that they were historical artefacts or old medical books.
Asked what USP–NF contains, 60% chose the best answer, tests for drug substances, ingredients and products. Drug ingredients were chosen by 65%. A widespread misconception, held by 62%, was that the compendia contain a list of all drugs approved by the FDA, but sponsors are not legally required to submit monographs for all new drugs to USP, and USP continuously works to add new monographs and update the compendia. Generic manufacturers' reliance on compendial monographs may help to explain why 43% associated the compendia with generic drug information. Of the respondents, 17% said the compendia contain master recipes for drugs, which reflects historical but not modern uses. Another misconception, held by 35%, was that compendial science involves dispensing; USP began publishing USP Dispensing Information in 1980, which was technically a dispensatory or list of approved drugs rather than a compendium, and sold it to The Thompson Company in 1998.
In true-or-false questions, 32% believed that the US government, through the FDA, publishes and revises USP–NF. A slim majority, 55%, knew that drugs named in the compendia must pass USP–NF tests. The survey's discussion states instead that more than half of respondents did not know that medicines must pass compendial tests. Of the respondents, 52% misidentified the usual sources of tests for adulteration, in a question that asked whether analysts testing medicines for adulteration, contamination or potency must rely on information from the drug's manufacturer or information the manufacturer authorises the FDA to use. Of the respondents, 79% knew that USP–NF contains tests for dissolution, chromatography and the like.
Only 8% of respondents used the compendia regularly, while 22% did not use them on a regular basis, 22% had seen but not used them, and 48% had neither seen nor used them. This limited familiarity may reflect the sample's mix of regulatory and non-regulatory writers rather than biomedical writers at large. The survey went to AMWA members, some of whom live outside North America, and did not specifically assess writers in other parts of the world.
The respondents had some sense of compendial science and the modern compendia, but this understanding seems coloured by historical precedents rather than current applications. Some of the misunderstandings may arise from historical developments that do not reflect modern uses of the compendia, such as the association of compendia with old texts, lists of drugs, recipes for making pharmaceuticals and dispensing information. The findings suggest that biomedical writers often do not understand or consider compendial science and USP in conjunction with their work.