Robert G. Sussman

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Guidance on the establishment of acceptable daily exposure limits (ADE) to support Risk-Based Manufacture of Pharmaceutical Products

Health-based limits for active pharmaceutical ingredients (API) referred to as acceptable daily exposures (ADEs) are necessary to the pharmaceutical industry and used to derive acceptance limits for cleaning validation purposes and evaluating cross-carryover. ADEs represent a dose of an API unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. Derivations of ADEs need to be consistent with ICH Q9 as well as other scientific approaches for the derivation of health-based limits that help to manage risks to both product quality and operator safety during the manufacture of pharmaceutical products. Previous methods for the establishment of acceptance limits in cleaning validation programs are considered arbitrary and have largely ignored the available clinical and toxicological data available for a drug substance. Since the ADE utilizes all available pharmaceutical data and applies scientifically acceptable risk assessment methodology it is more holistic and consistent with other quantitative risk assessments purposes such derivation of occupational exposure limits. Processes for hazard identification, dose response assessment, uncertainty factor analysis and documentation are reviewed.

A harmonization effort for acceptable daily exposure application to pharmaceutical manufacturing – Operational considerations

A European Union (EU) regulatory guideline came into effect for all new pharmaceutical products on June 1st, 2015, and for all existing pharmaceutical products on December 1st, 2015. This guideline centers around the use of the Acceptable Daily Exposure (ADE) [synonymous with the Permitted Daily Exposure (PDE)] and operational considerations associated with implementation are outlined here. The EU guidance states that all active pharmaceutical ingredients (API) require an ADE; however, other substances such as starting materials, process intermediates, and cleaning agents may benefit from an ADE. Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE. Established methodologies such as occupational exposure limits or bands (OELs or OEBs) and the threshold of toxicological concern (TTC) can be used or adjusted for use as interim ADEs when only limited data are available and until a more formal ADE can be established. Once formal ADEs are derived, it is important that the documents are routinely updated and that these updates are communicated to appropriate stakeholders. Another key operational consideration related to data-poor substances includes the use of maximum daily dose (MDD) in setting cross-contamination limits. The MDD is an important part of the maximum allowable/safe concentration (MAC/MSC) calculation and there are important considerations for its use and definition. Finally, other considerations discussed include operational aspects of setting ADEs for pediatrics, considerations for large molecules, and risk management in shared facilities.

Developing Acceptable Surface Limits for Occupational Exposure to Pharmaceutical Substances

Acceptable surface limits (ASLs) are developed in order to establish a quantitative measure for the potential risk from exposure by dermal contact. In the pharmaceuticals industry, ASLs are used for protection against active pharmaceutical ingredients that are known to cause pharmacological or toxicological effects. An ASL can be used, together with appropriate analytical methods and industrial hygiene monitoring, to assess workplaces for potential dermal exposure and to protect the health and safety of individuals who might come in direct contact with contaminated surfaces in the workplace. ASLs are also used to evaluate the adequacy of housekeeping measures and the effectiveness of engineering containment approaches, or to determine whether a chemical is present on surfaces where it is not intended to be (e.g., in lunch rooms or offices, or on the outside surfaces of packaging materials). However, they should not be confused with cleaning limits for the surfaces of manufacturing devices that might come into contact with the drug product, which are set to minimize cross contamination between drug products and to protect end-users (e.g., patients taking drug products) as opposed to workers. A number of parameters must be evaluated in order to accurately develop appropriate and scientifically supportable limits. These include the dose or concentration that will cause the potential effect, the degree of chemical transfer from contaminated surfaces to the skin, and the rate or amount of percutaneous absorption. In practice, this information is usually limited or unavailable. Additionally, there has been very little regulatory guidance on the setting of ASLs. Consequently, in order to calculate an ASL, various assumptions must be made by health and safety professionals regarding how dermal exposures might occur. As quantitative data become available, the ASL can be adjusted accordingly. An overview of the setting of health-based and performance-based ASLs for pharmaceutical substances from animal and human toxicological data is provided.