Old Polymorph, New Technique: Assessing Ritonavir Crystallinity Using Low-Frequency Raman Spectroscopy.

Two decades ago, postmarket discovery of a second crystal form of ritonavir with lower solubility had major implications for drug manufacturers and patients. Since then, ritonavir has been reformulated via the hot-melt-extrusion process in an amorphous form. Here, quantitative low- and mid-frequency Raman spectroscopy methods were developed to characterize polymorphs, form I and form II, in commercial ritonavir 100 mg oral tablets as an alternate analysis approach compared to X-ray powder diffraction (XRPD). Crystallization in three lots of ritonavir products obtained from four separate manufacturers was assessed after storage under accelerated conditions at 40 °C and 75% relative humidity (RH). Results were compared with quantitative XRPD methods developed and validated according to ICH Q2 (R1) guidelines. In a four-week open-dish study, form I crystallization occurred in two of the four products and form II crystallization was detected in another ritonavir product. The limits of detection for XRPD, low-frequency Raman (LFR), and mid-frequency Raman (MFR) were determined to be 0.7, 0.8, and 0.5% for form I and 0.6, 0.6, and 1% for form II, respectively. Root-mean-squared-error of predictions were 0.6-1.0 and 0.6-2.5% for LFR- and MFR-based partial least-squares models. Further, ritonavir polymorphs could also be identified and detected directly from ritonavir tablets using transmission LFR. In summary, LFR was applied for the assessment of polymorphism in real-world samples. While providing analytical performance similar to conventional techniques, LFR reduced the single measurement time from 66 min (XRPD) to 10 s (LFR) without the need for tedious sample preparation procedures.

FDA/M-CERSI Co-Processed API Workshop Proceedings.

These proceedings contain presentation summaries and discussion highlights from the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) Workshop on Co-processed API, held on July 13 and 14, 2022. This workshop examined recent advances in the use of co-processed active pharmaceutical ingredients as a technology to improve drug substance physicochemical properties and drug product manufacturing process robustness, and explored proposals for enabling commercialization of these transformative technologies. Regulatory considerations were discussed with a focus on the classification, CMC strategies, and CMC documentation supporting the use of this class of materials from clinical studies through commercialization. The workshop format was split between presentations from industry, academia and the FDA, followed by breakout sessions structured to facilitate discussion. Given co-processed API is a relatively new concept, the authors felt it prudent to compile these proceedings to gain further visibility to topics discussed and perspectives raised during the workshop, particularly during breakout discussions. Disclaimer: This paper reflects discussions that occurred among stakeholder groups, including FDA, on various topics. The topics covered in the paper, including recommendations, therefore, are intended to capture key discussion points. The paper should not be interpreted to reflect alignment on the different topics by the participants, and the recommendations provided should not be used in lieu of FDA published guidance or direct conversations with the Agency about a specific development program. This paper should not be construed to represent FDA's views or policies.

An Evaluation of US Food and Drug Administration's Program to Register HIV Drugs for Use in Resource-Constrained Settings.

Importance: The US Food and Drug Administration (FDA) program to review antiretroviral drugs for use in low-resource settings via the US President's Emergency Plan for AIDS Relief (PEPFAR) now supports treatment of more than 14 million patients with HIV. However, an in-depth evaluation of the program has not been undertaken. Objective: To conduct a quantitative analysis of the FDA-reviewed antiretroviral drug applications in order to assess the contributions of PEPFAR and to identify areas for improvement. Design, Setting, and Participants: A cross-sectional study was conducted of all PEPFAR applications submitted to the FDA from December 1, 2004, to May 31, 2018. The analyses were conducted between October 2018 and February 2019. Main Outcomes and Measures: Numbers and types of applications reviewed, how long it took for applications to obtain approval or tentative approval (time to registration), how often the FDA issued a complete response letter (CRL) identifying deficiencies precluding application approval or tentative approval and their reasons, and the association between CRLs and time to registration. Results: Overall, 260 PEPFAR applications for 327 antiretroviral therapies were reviewed by FDA, of which 216 applications (83%) for 272 drugs were authorized for use. Of the 216 authorized applications, 184 applications for 231 drugs remain in active status and, thus, are available for use. Twenty-six percent (56 of 216) of the applications were for pediatric-specific formulations or strengths; the remainder were for adults. For all 216 applications, the median (interquartile range) time to registration was 10.0 (7.0-17.5) months. Thirty-seven percent (95 of 260) of the applications received 1 or more CRLs, resulting in a total of 172 CRLs; most applications received 1 CRL, whereas some were issued up to 6 CRLs. Among all CRLs, 264 deficiency reasons were identified; the most common deficiencies were associated with manufacturing processes (155 [44%]), followed by product labeling (62 [23%]), and failing facility inspections (54 [20%]). Complete response letters were associated with an increased time to registration. Applications without CRLs had a median (interquartile range) time to registration of 9.0 (5.5-12.0) months, whereas those with at least 1 CRL took a median (interquartile range) of 22.0 (14.0-38.0) months (P < .001). Conclusions and Relevance: The FDA's PEPFAR program has made many antiretroviral drugs available for global use. However, FDA and the pharmaceutical companies could take steps to improve the quality of applications submitted to prevent avoidable deficiencies in manufacturing processes and labeling. Further efforts to develop better, easier to use pediatric-specific therapies are needed.

Impact of the US Food and Drug Administration registration of antiretroviral drugs on global access to HIV treatment.

BACKGROUND: Since 2004, the US Food and Drug Administration's (USFDA) dedicated drug review process in support of President's Emergency Plan for AIDS Relief (PEPFAR) has made safe, effective and quality antiretrovirals (ARVs) available for millions of patients. Furthermore, the WHO and Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) can add the USFDA-reviewed products to their respective formularies, through a novel process of 'one-way reliance'. We assessed the number of ARVs made available through WHO and Global Fund based on the USFDA review. METHODS: We conducted a cross-sectional study of all the USFDA-reviewed PEPFAR drugs between 1 December 2014 and 20 March 2017 to determine 1) the percentage that are included on the WHO and Global Fund formularies; 2) the number of the USFDA ARVs supporting the WHO HIV treatment guidelines, and their uptake by WHO and Global Fund and 3) time between the USFDA review and WHO review of the same ARVs. FINDINGS: Overall, 91% (204/224) of the USFDA products appeared on either the WHO/Prequalification of Medicines Programme (PQP) or the Global Fund ARV lists. Forty-five per cent (100/224) and 83% (184/224) appear on WHO/PQP and Global Fund formularies through one-way reliance, respectively. Forty-one per cent (91/224) of the USFDA products support the WHO-preferred first-line HIV treatment options. Of these 91 products, 38% and 85% of products were adopted by WHO/PQP and Global Fund through one-way reliance, respectively. Sixty-six products that were fully reviewed and registered by WHO (vs one-way reliance) had also undergone the USFDA review; 46 of these were registered by WHO after the USFDA review was complete (median delay of 559 days (IQR 233-798 days)). CONCLUSIONS: The USFDA's PEPFAR process is making safe and effective ARVs available worldwide, in part because the major global ARV procurement organisations rely on the USFDA registration as proof of quality. There is room for improved information sharing and collaboration to reduce duplication of effort, save resources and further expedite access to ARVs.

The US Food and Drug Administration's tentative approval process and the global fight against HIV.

INTRODUCTION: In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. DISCUSSION: USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. CONCLUSIONS: In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource-constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example.