This article is republished with permission from the February 2012 PDA Letter.
The standards that the United States Pharmacopeia (USP) develops are enforceable by the U.S. FDA and are relied upon in more than 130 countries. While these standards have helped ensure public health throughout the world, recently the USP has published some general information chapters that have generated, according to some, a unnecessary strain on pharma’s resources. In addition, USP has proposed chapters that duplicate existing regulations/guidance and some USP chapters that go beyond USP’s scope.
These issues being introduced by USP prompted the formation of the Pharmacopeial Interest Group and will require the immediate attention of its members. The Interest Group will focus on compendial issues impacting our industry. The purpose of the group is to serve as the liaison between the Regulatory Affairs/Quality Advisory Board (RAQAB) and pharmacopoeias. The Pharmacopeial Interest Group will focus mainly on the major pharmacopoeias of the world: USP, Ph Eur, JP, Indian Pharmacopeia, Chinese Pharmacopoeia, Brazil Pharmacopoeia.
Specifically, the group is charged with:
1. Monitoring compendial activities and publications and provide periodic reports to RAQAB
2. Preparing position papers on compendia initiatives and proposals not being addressed by other PDA Committees
3. Representing PDA at the USP Stakeholders Forum
4. Proactively identify compendial topics and advocate PDA’s position
It is scheduled to meet for the first time at PDA’s Annual Meeting in Phoenix, Ariz.
On January 4, USP announced that it was seeking feedback on a proposed general information chapter, entitled, USP General Chapter <1083> Good Distribution Practices—Supply Chain Integrity. According to USP, the new proposed standard will not be mandatory. In addition, there have been recent proposals for new general chapters covering the spectroscopic techniques of mid-Infrared (<854> and <1854>), UV/ Visible (<857> and <1857>) and Atomic Absorption (<852> and <1852>). These new General Chapters are proposed to collectively replace <851> Spectropho tometry and Light-Scattering. The USP has also proposed new requirements for instrument qualification and procedure validation/verification and is in the process of revising the Heavy Metals chapters to utilize inductively coupled plasma technology*, not commonly used by industry for QC release.
*This is an analytical technique used for the detection of trace metals in environmental samples. The primary goal of ICP is to get elements to emit characteristic wavelength specific light which can then be measured.
With all these changes affecting broad scope procedures and methodology, it is important for industry to make sure the items being introduced by USP are appropriate or even if it is appropriate for USP to make standard-setting processes for these types of issues. It is also important to question if this is the purpose or mandate of a pharmacopoeial today.
USP has introduced the Medicines Compendia which is intended for use by healthcare practitioners outside the United States. According to the USP website, the rationale for establishing this new compendium is because public standards are critically important, especially where regulatory and compendia resources are constrained or absent. The USP Medicines Compendium (MC) represents a novel approach to bring good public standards—monographs with reference materials—into the public domain as early as possible after access in a national market. Reliance on these standards can occur at the time of approval through regulatory decision-making and allows marketplace surveillance by manufacturers, purchasers, and the regulatory authority itself. Without the public monograph, some regulatory agencies may need to conduct the same kind of review that is accomplished independently by the USP Council of Experts. The MC thus reinforces the use of good quality standards by ethical manufacturers and can conserve scarce regulatory resources. The MC can become one of a series of safety nets that help combat counterfeit and substandard medicines.
Though the USP Medicines Compendium Frequently Asked Questions says that standards in the MC are developed in an open, transparent process that seeks public comment–similar to the wellestablished process by which USP’s other compendial standards are developed,” the USP website says: USP MC standards are reviewed and approved by Expert Committees of USP’s Council of Experts. These Expert Committees follow all applicable rules and procedures of the Council of Experts, although the process may differ from that for other USP compendium.
In our opinion, this seems like the Medicines Compendia is opening the door to bypass the comment process and set standards without the input of industry and proper review. The rules and procedures of the current Council of Experts in section 7.02 states accelerated revision processes are used to make revisions to the USP-NF official more quickly than through USP’s standard revision process when necessary to correct errors, address patient safety issues, or resolve compliance issues. Such accelerated revisions, which include Interim Revision Announcements, Revision Bulletins and Errata, do not always require notice and comment and allow for a revision to become official prior to the next USP-NF or Supplement. Accelerated revisions may be used only in the circumstances described in USP’s Guideline on the Use of Accelerated Processes for Revisions to the USP–NF, which is posted on USP’s website.
It goes on to say: all proposals for revisions to the USP-NF* shall, at the direction of either an Expert Committee, or the Scientific Liaison (following notice to the appropriate Expert Committee), be published in the Pharmacopeial Forum (PF) for public review and comment. Unless otherwise determined by USP, a proposal that includes the use of a new USP Reference Standard shall not be scheduled for publication in PF until a suitable reference standard bulk candidate has been received by USP.
*The United States Pharmacopeia– National Formulary (USP–NF) is a book of public pharmacopeial standards. It contains standards for medicines, dosage forms, drug substances, excipients, medical devices, and dietary supplements.
However, in the case of monographs for the Medicines Compendia, it says, except in rare cases where the MC Expert Committee(s) determine that a new or revised standard should be made available immediately because of an urgent public health need, all proposals to revise the MC shall be published in draft on the MC web site, and provide an adequate period for public review and comment.
To ensure an active voice in the USP process, industry must take the time to participate in the USP commenting process. The public review and comment process starts with a proposed change to an existing standard or introduction of a new standard and ends when that standard is officially adopted. Often this change is intended to improve the official criterion or procedure.
To understand the importance for the need to comment, we should look back to the changes and implementation made to the residual solvents requirements. The origin of the residual solvent requirement can be traced back to 1988 when USP proposed a general test chapter for organic volatile impurities (OVI), ultimately adopted in 1990.
In 1997, ICH finalized document Q3C, titled, Impurities: Guideline for Residual Solvents Applicable to New Drug Substances, Excipients and Products. The European Pharmacopoeia (Ph. Eur.) subsequently adopted this guideline in 2000. In 2003, the USP published a proposal in the PF to revise the chapter on OVIs and align it with the ICH and Ph. Eur. documents. The official adoption date for this revision was to be April 1, 2004, and the proposed revision that would include a line item for residual solvent testing in every monograph, was discussed at the USP Annual Scientific and Stakeholder Forum meetings held in September 2004.
The feedback provided at these two venues prompted a major revision and ultimate delay in the adoption of the standard. Industry publicly commented that the inclusion of this requirement in all monographs would result in unnecessary testing. The rationale for this statement was based on the premises that:
1) If a monograph calls for a test, then a result or value must be generated and
2) excipients, drug substances or dosage forms that do not use residual solvents during the synthesis or formulation processes would not need to be tested.
Based on the public feedback, USP revised their initial proposal and formed a project team that would meet and make recommendations on how this new proposed standard should be adopted.
It is important to keep in mind that the USP requirement is not limited to new drug substances, excipients or products but encompasses previously approved items. This distinction is critical, because it meant that previously unknown information would need to be collected, investigated and assessed for approved marketed products. Since many of these products were developed before the ICH requirement was adopted, much of the information required to meet the new USP requirement was unknown. The USP understood this argument presented by industry and began working with the pharmaceutical community to develop education and training programs that would help industry implement the requirement with limited disruption. This collaborative effort culminated with the adoption of the standard in the USP-NF on July 1, 2008 with little or no comment from industry. This is not to imply there were not issues after the standard finally became official. However, the remaining issues are more about the applicability of the standard and not about the content.
The public review process is an important mechanism for USP in obtaining necessary feedback from the industry regarding changes to the official standard-setting processes. It is important for industry to be aware of and participate in the process to assure the standard ultimately adopted is suitable and appropriate. As mentioned earlier, there are a number of broad scope issues currently under revision and adoption in the USP.
The lessons learned from the residual solvents case are meant to provoke industry into actively participating in the standard-setting process by reviewing and commenting on the proposed revisions to ensure they meet the needs of the industry. There are a number of ways industry may comment on proposed changes in the USP. These include commenting as an individual, as part of a company or as a member of a trade organization. The timeliness of the formation of the interest group in light of current developments at USP will offer PDA members a vehicle for commenting on concerns regarding apparent deviation from a pharmacopoeial mandate and entry into areas where there are already sufficient resources and noted authorities acting and writing guidance for industry.
Susan Schniepp is the Vice President of Quality for OSO BioPharmaceuticals Manufacturing, a contract manufacturing organization for sterile injectables. She has 30 years of industry experience in quality control and quality assurance. During her career, she has had responsibilities for complaints, labeling, investigations, compendial affairs and other quality systems. Sue is also a member of Regulatory Affairs/Quality Advisory Board, the PDA Letter Editorial Committee and has presented at many PDA venues.
Janeen Skutnik-Wilkinson is the Director of Quality Policy at Pfizer. She is the past chair of IPEC Americas and has been involved in IPEC as Chair of the Compendial Review committee from 1998-2007. She has given many presentations on excipients in various countries over the past decade and a half. Janeen has also been the chair of PhRMA’s Compendial Liaison Committee since 1998 and was the Topic Leader for ICH Q4B on Pharmacopeial Interchangeability. She has been a member of PDA for many years and a speaker at several PDA meetings and conferences both in the USA and Europe. Janeen is also a member of the Regulatory Affairs/Quality Advisory Board and the PDA Letter Editorial Committee.
This article is republished with permission from the February 2012 PDA Letter. www.pda.org/pdaletter