Todd L. Cecil

FIP/AAPS Joint Workshop Report: Dissolution/ In Vitro Release Testing of Novel/Special Dosage Forms

In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors acknowledge and expect further updates to be made as additional progress is made in the relevant areas. Thus, comments and additional contributions are welcome and may be considered for the next revision of the position paper.

Metal Impurities in Food and Drugs

The major metals of potential health concern found in food, drugs (medicines), and dietary supplements are lead, cadmium, mercury, and arsenic. Other metals, such as chromium, copper, manganese, molybdenum, vanadium, nickel, osmium, rhodium, ruthenium, iridium, palladium, and platinum, may be used or introduced during manufacturing and may be controlled in the final article as impurities. Screening for metals in medicines and dietary supplements rarely indicates the presence of toxic metal impurities at levels of concern. The setting of heavy metal limits is appropriate for medicines and is appropriate for supplements when heavy metals are likely or certain to contaminate a given product. Setting reasonable health-based limits for some of these metals is challenging because of their ubiquity in the environment, limitations of current analytical procedures, and other factors. Taken together, compendial tests for metals in food and drugs present an array of issues that challenge compendial scientists.

The value of USP public standards for therapeutic products.

The word pharmacopeia means to make a drug. Before the Food and Drug Administration (FDA) and modern pharmaceutical manufacturing, virtually all medicines in the United States were prepared by physicians or pharmacists. Medicines were prepared in the early years of the Republic according to a number of publications—pharmacopeias and dispensatories—from this country and abroad. These differing approaches, coupled with the absence of laws regulating either the practice of medicine and pharmacy or the medicinal preparations used, led to irregularities in how medicines were prescribed, prepared, dispensed, and administered. This lack of consistency was widely recognized then, as it is now, as a barrier to quality medical care. It prompted agreement by a group of physicians to create a national pharmacopeia. These physicians held the first United States Pharmacopeial (USP) Convention in 1820 in the Capitol Building of the United States (1). Delegates representing regional medical societies and schools arrived in Washington, D.C., to determine the contents of the first Pharmacopoeia of the United States of America (USP), which presented the best medicines, named and provided recipes for their preparation, and gave instructions for their use. Over time, with the rise in modern pharmaceutical manufacturing, the task of making a drug has shifted from practitioners to pharmaceutical manufacturers. A residuum of the original approach remains with practitioners who compound a medicine, using at times a USP preparation monograph pursuant to a physician’s prescription. But only a relatively small fraction of prescriptions in the United States are compounded. USP was incorporated under the laws of the District of Columbia in 1900. It is a 501(c)(3) corporation working in the public interest. The USP Convention meets at 5-year intervals, when it elects its governing body, the Board of Trustees, and its standards-setting body, the Council of Experts. With staff support, the Council of Experts creates the content for the United States Pharmacopeia–National Formulary (USP– NF). With the exception of staff, all participants in USP, the convention members, members of the Board of Trustees, and the Council of Experts work as volunteers. USP has strict conflict-of-interest rules and also confidentiality rules that protect sensitive commercial and trade secret information that is provided by sponsors of monograph and General Chapter proposals. Although several public health laws controlling biologicals and drugs were created in the early part of the twentieth century in the United States, modern regulatory control really began with passage of the Federal Food, Drug, and Cosmetic Act (FFDCA) in 1938. This act incorporated prior legislation and created the FDA. FDA regulates pharmaceutical manufacturing closely. USP–NF has evolved in concert with these changes to become a book of public standards. The modern pharmacopeia is presented as two compendia, the original USP and, more recently, the NF. In 1975, USP purchased the NF, a compendium of public standards primarily for excipients. These are now published annually as a combined text, USP–NF, with two annual Supplements. The current edition, USP 27–NF 22, became official in January 2004 and contains monographs for prescription and over-the-counter (OTC) drugs, biologicals, dietary supplements, and allied therapeutic products (including some devices). Excipient monographs continue to appear in NF. The two compendia are named in the FFDCA as official compendia of the United States (2). The FFDCA integrates USP standards in the adulteration and misbranding provisions for drug products. Section 501(b) of the act provides that a drug is adulterated if it is recognized in USP–NF and does not adhere to USP–NF standards or does not state on the label how the drug strength or purity differs from these standards. Section 502(g) of the act states that a drug is misbranded if it is recognized in USP–NF and does not meet USP–NF packaging and labeling requirements set forth. Section 502(e) requires that the established name of the drug must appear on the label and states that the established name of a drug or ingredient is the one appearing in USP–NF. The modern USP–NF now comprises more than 4000 monographs for named ingredients and products, which are termed articles, as in articles of commerce. This is also how 1 United States Pharmacopeia, Rockville, Maryland 20852, USA. 2 J. P. Boehlert, E. M. Cohen, J. E. DeMuth, M. C. Frederiksen, H. G. Klein, R. M. Russell, P. L. Schiff, S. S. Seaver, A. M. M. Shepherd, S. Stavchansky, T. J. Wozniak, and Dr. Williams (ex officio chair). 3 To whom correspondence should be addressed. (e-mail: rlw@ usp.org) Pharmaceutical Research, Vol. 21, No. 10, October 2004 (© 2004)

Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms—Workshop Report

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.

Oral Dosage Form Performance Tests: New Dissolution Approaches

No HeadingThe performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsor’s Request for Revision to USP, the USP’s Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.

Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing

USP Dissolution specifies performance verification testing (PVT) of dissolution Apparatus 1 and 2. Acceptance criteria are determined from a collaborative study and apply per tablet; i.e., each of the six tablets tested must fall within the specified acceptance criteria in order to pass. In this Stimuli article, USP proposes changing the form of the acceptance criteria to one that is consistent with the International Organization for Standardization’s (ISO’s) recommendations for proficiency testing. The new criteria would apply to the laboratory’s average and standard deviation of the tablets tested. The article explains the rationale and shows the criteria that would be applied to USP Lot P Prednisone Reference Standard (RS) Tablets and USP Lot Q Salicylic Acid RS Tablets.

USP Responses to Comments on Stimuli Article, "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing"

Pharmacopeial Forum 33(3) [May–June 2007] included a Stimuli article titled “Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing.” This Stimuli article proposed changing the form of the acceptance criteria for the Performance Verification Test (PVT) associated with USP Dissolution to make the PVT consistent with the International Organization for Standardization’s recommendations for proficiency testing. The article elicited five comments, which are abstracted here with USP responses.

Progressively Reducing Regulatory Burden

Principles of dissolution science have been applied to allow waiver of in vivo bioequivalence studies for oral immediate release solid dosage forms, providing certain stipulations are met. This approach reduces regulatory burden without sacrificing product quality and performance requirements that assure continuing equivalence. These principles are broadly applicable to other dosage forms and routes of administration. In this article, we postulate a further opportunity, which relies on a determination of “optimal performance” for nonsolution orally administered drug products. The determination can be applied to certain highly soluble and rapidly dissolving drug products without further study, paving the way possibly for even further reductions in regulatory burden.

Meeting Report: FIP/AAPS Joint Workshop Report: Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms

In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors Please send comments to the Co-Chairs of the FIP Dissolution/Drug

Validation of procedures for elemental impurities

In recent years, the concern about the toxicity of trace elements in foods and drugs has increased significantly. Four elements—mercury, arsenic, cadmium, and lead—have been specifically targeted for increased levels of control because of this toxicity. To measure these elemental impurities, the application of advanced spectroscopic procedures has been necessary. The procedures provide tremendous gains in sensitivity, but may suffer from specificity and precision issues. The choice of the procedure often will involve a trade-off between these important parameters and the United States Pharmacopeia (USP) has provided a means by which to evaluate this trade-offs without giving up the data quality. This chapter examines the two different validation approaches as applied to the evaluation of a sample for the trace elemental impurity contamination. These approaches examined include the traditional validation approach and the USP approach. In addition, the chapter provides some best practices and common sense approaches to validation of these types of procedures.