In pharmaceutical development and production, multiple regulatory guidelines have been established for laboratories and manufacturing environments by local, regional, and international pharmacopoeias. These frameworks are further overseen by organizations and agencies.
Supporting organizations, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and World Health Organization (WHO), play a critical role in liaising between various pharmacopoeias in an attempt to harmonize monographs and technical standards.
However, even with guidance from such organizations, it is important for laboratories and production processes to maintain an understanding of which guidelines pertain to their monographs within their respective target markets, and to the agencies that they must report. Lack of clarity on guidelines can slow the process of obtaining authorization to market a given drug, and possibly lead to fines or other forms of reprimand from regulatory agencies.
In this article, we will define what constitutes a modern pharmacopoeia and discuss, at length, the specific roles of the ICH and WHO.
ICH - Leading the way
The WHO collaborates with the ICH in an effort to standardize pharmaceutical formulations. The ICH was established with the goal of harmonizing guidelines between local, national, and international pharmacopoeias. As an organization, it follows a mission of ensuring that “safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.”
Pharmaceutical companies looking to release a new medication, for example, face certain requirements for analytical methods and other regulated steps of the development process. In order to make marketing authorization more efficient, the ICH has developed guidelines that involve scientific consensus between regulatory and industry experts. This facilitates technical research and development approaches, and encourages the implementation and integration of common standards via dissemination of information and coordination of guidelines.
A number of influential national and continental organizations are involved in the ICH, including the European Commission (EC, Europe), the Food and Drug Administration (FDA, USA), the Japanese Ministry of Health, Labour and Welfare (MHLW/PMDA), Health Canada, Swissmedic (Switzerland), and many more. Leadership and members span all corners of the industry, and can include scientists, political affairs and public health specialists, attorneys, etc. Specific guidelines and regulatory activities of these organizations range from technical and scientific standards for manufacturing to general oversight of the development and production of food, drugs, medical devices, radiation-emitting products, vaccines, blood products, biologics, animal and veterinary pharmaceuticals, cosmetics, and tobacco products.
Regular activities of the ICH are divided into four main categories, each of which are briefly described below. Initiation of any of the four categories begins with a “concept paper” submitted by a member organization. This paper consists of a summary of the proposal for a new harmonisation activity – a document defining how to unify the process of developing, manufacturing, marketing, and distributing consumer-directed products.
- Formal ICH Procedures: Identify a new topic related to harmonization efforts of the ICH.
- Q&A Procedures: Involve situations in which there may be clarification or additional scope of details required regarding an existing ICH guideline.
- Revision Procedures: Pertain to out-of-date or invalid content of an existing ICH guideline, or times in which there may be new information that must be added to an existing ICH guideline.
- Maintenance Procedures: Relate to changes that need to be made to a guideline with a maintenance procedure.
A fifth, separate activity of the ICH involves implementation of new guidelines. This is accomplished with the input of ICH Regulatory Members and Observers; it is intended that all ICH Regulatory Members should implement the full spectrum of ICH guidelines; in fact, implementation of certain guidelines is required for membership at this level.
The ICH does, however, realize and account for the fact that in certain instances, guidelines must be subject to varying degrees of implementation, based on factors like geographic location, cultural differences, and access to resources. It is possible for anyone, industry stakeholders and members of the general public alike, to search for the status of implementation of guidelines by ICH members on the ICH web site.
Different sources attribute the establishment of pharmacopoeias to various times and creators. According to some, the term “pharmacopoeia” dates back to the 15th century in Italy, when a physician named Lodvice dal Pozzo Toshchanelli took it upon himself to devise a book of “drug formulas” for a group of local pharmacists.
Others say it was Dr. A. Foes, of Switzerland, who first created the pharmacopoeia in 1561. Either way, several centuries later, in 1820, a group of American physicians eventually published the first iteration of the United States Pharmacopeia (USP) out of concern for the quality and consistency of medications that were becoming available to the public.
Six decades later, in 1888, the American Pharmaceutical Association then drafted the National Formulary (NF), which supported the USP with “formulations and unofficial preparations” of various pharmaceutical products. In 1906, the United States went on to pass the well-known Federal Food and Drugs Act. This act helped formally delineate whether a pharmaceutical compound met federal purity standards or was considered “adulterated,” based on its similarity to compounds named in the USP and NF.
Many years of talks and preliminary committees subsequently ensued, and, as mentioned earlier, the first edition of the WHO’s International Pharmacopoeia was published in 1951. This compendium is recognized to more or less supersede all other pharmacopoeias, and serves to outline “international standards” of drug compounding, including less technically demanding alternatives where needed, for adoption by Member States. Its goal is to “help achieve a potentially global uniformity of quality specifications for selected pharmaceutical products, excipients, and dosage forms.”
Thanks in large part to the leadership efforts of the ICH (discussed below) and WHO, the role of a modern pharmacopoeia is better understood now than it has been in the past. According to the WHO, a pharmacopoeia is formally defined as a “legally binding collection, prepared by a national or regional authority, of standards and quality specifications for medicines used in that country or region.”
The WHO goes on to define quality specifications as “appropriate tests that confirm the identity and purity of the product, ascertain the strength (or amount) of the active substance and, when needed, its performance characteristics.” Reference substances, on the other hand, are defined as “highly characterized, physical specimens... used in testing to help ensure the quality, such as identity, strength, and purity, of medicines.” Pharmacopoeia monographs - or drug “recipes,” of sorts - discuss pharmaceutical starting materials as well as excipients, intermediates, and finished pharmaceutical products (FPPs).
According to the WHO, there are more than 140 independent countries participating in 30 national pharmacopoeias, plus those representing the greater African, European, and International Pharmacopoeias.
No matter how large or small, each pharmacopoeia should have guidelines detailing all steps of the drug development process, from monographs to research methods and technical standards. The goal is to ensure that GMPs (“Good Manufacturing Practices”) are met, ensuring the safety, purity, and effectiveness of drugs, cosmetics, food products, and more. The International Pharmacopoeia, for example, has monographs that exist for “active pharmaceutical ingredients (APIs), excipients, herbal products, biologics (antibody, cell, and gene therapies; vaccines; blood products), radiopharmaceuticals, dosage forms, and homeopathic preparations,” as well as medical devices and dietary supplements. The WHO also publishes a Model List of Essential Medicines within its International Pharmacopoeia, which focuses on compounds of great importance to global and public health, such as those used to treat malaria, tuberculosis, HIV/AIDS, and those medicines used to treat children.
It has been said that pharmacopoeias should, by all reasonable standards, have their own lab, regardless of whether or not they formally contribute to larger publications such as the International Pharmacopoeia. The British Pharmacopoeia lab, for example, supports the work of its commission by procuring, establishing, and maintaining British Pharmacopoeia Chemical Reference Substances (BPCRS), which are used in development of BP monographs.
Since the ultimate goal of the ICH and WHO is harmonization of guidelines, it has been agreed that a pharmacopoeia document or chapter is considered fully harmonized when a substance or product being tested “yields the same results and the same accept/reject decision,” by the analyst, “regardless of which pharmacopoeia is referenced.” This is called “interchangeability.” According to WHO guidelines, each pharmacopoeia must identify which monographs are fully harmonized within their publication.
Additional goals of pharmacopoeia participation include the proposal and exchange of new compounding techniques, whether it’s analytical fingerprinting or non-destructive approaches to spectroscopy and imaging. While Member States can generally be relied upon to act in good faith regarding all of the aforementioned activities, it is typically up to regulatory agencies to ensure that pharmacopoeia guidelines are followed closely.
Pharmacopoeias provide guidelines, but it remains the job of regulatory agencies, not the pharmacopoeias themselves, to determine whether the guidelines are being followed. This can be somewhat challenging for pharmaceutical companies, which may have to abide by pharmacopoeia and ICH/WHO guidelines in several drug destination markets at once. While attempts at harmonization are always underway, guidelines don’t always align. Oftentimes this means ensuring that the product meets guidelines set forth by the pharmacopoeias for each of the respective areas, plus consideration of ICH or WHO guidelines on top of those described in monographs from local or regional pharmacopoeias.
In most developed parts of the world, various countries and/or continents have their own pharmacopoeias. The European Pharmacopoeia (Ph.Eur.) has specific chapters relating each of its monographs to overarching ICH guidelines; in the United States, the FDA has also issued guidelines for this purpose. ICH guidelines are also transferred into national or regional regulation; in the US, this is done by the FDA, and in the UK, it is handled by the European Medicines Agency EMA/MHRA.
To further illustrate this point, the US Pharmacopoeia and National Formulary, for example, are governed and held adherent to regulations set forth by the Federal Food, Drug, and Cosmetic Act (FDCA). The FDCA recognizes both the USP and NF as “official compendia,” meaning that any drug named in the USP-NF must “comply with compendial identity standards or be deemed adulterated, misbranded or both.” Enforcement of compendial standards is not overseen by the US Pharmacopoeia itself; rather, it is the responsibility of the FDA and other government authorities to enforce the guidelines of the USP, per section 2.30 (“Legal Recognition”) of the General Chapter of the United States Pharmacopoeia.
Within their target markets, regulatory agencies have the ultimate say in whether a product is allowable in its current form, with approved marketing. Regulatory agencies such as the FDA have the ability to issue sanctions or even demand that a drug is pulled from a market, if concerns arise.
It can prove challenging for labs to navigate the relationship between local and regional pharmacopoeias, harmonization efforts of the ICH and WHO, and oversight by regulatory agencies. While harmonization efforts and the leadership of the ICH and WHO have proven helpful in decreasing the prior variance and complexity in the drug development pathway for GMP-regulated labs, their interactions with individual pharmacopoeial monographs, as well as regulatory agencies, could often use a bit more explanation.
At this point, the ICH is continuing to work toward a goal of ensuring global translation of monographs is as seamless and consistent as possible. The WHO also helps to facilitate this on a worldwide scale. Finally, it is the regulatory agencies that maintain a close eye on labs and compounding pharmacies, to make sure the products being dispensed have the same composition, no matter where they are produced.
[Disclaimer: please note that this article reflects PerkinElmer’s interpretation of the respective roles of the ICH, regulatory bodies and pharmacopoeias. It is ultimately the customer’s responsibility to understand and fulfill GMP requirements.]
- The British Pharmacopoeia, www.pharmacopoeia.com
- United States Pharmacopoeia and National Formulary, 42nd edition, General Notices chapter. Section 2.30 (Legal Recognition)