Identifying marks

Identifying marks: advances in marking, coding, and inspection technology have led to new anticounterfeiting tools for drug makers trying to protect products that are in pill formSolid dosage form manufacturers have long relied on shape and color as well as on-pill imprints of

Get Your Wonder Drugs!

Get Your Wonder Drugs!: But do you know what it takes to produce them? - high costs of drug research and developmentHarry Howard almost made the biggest blunder of his life when he tossed the building blocks of a wonder drug

Generic makers are

Generic makers are seeing promise in field of biotech engineering - Generic drugs: special reportGeneric drug makers are knocking on a door that never has been opened. With a strong undercurrent

Drug Bust: Killing the

Drug Bust: Killing the golden goose - pharmaceutical price controls - Industry OverviewIn an unprecedented series of 60-second radio spots in Michigan last fall, the head of Pfizer's Ann

Promoting quality in drug manufacturing: FDA is re-engineering the CMC review process for innovator and generic drugs and backing risk-based ICH quality standards

Promoting quality in drug manufacturing: FDA is re-engineering the CMC review process for innovator and generic drugs and backing risk-based ICH quality standardsAs pharmaceutical manufacturing evolves from an art form to a science-based process, the Food and Drug Administration is eyeing opportunities to translate better information about product quality into more risk-based regulatory review and inspection policies. The over-ridingS goal is to apply a "quality by design" approach to pharmaceutical manufacturing to achieve the "desired state" of product quality and performance, explains Ajaz Hussain, deputy director of the Office of Pharmaceutical Science (OPS) in FDA's Center for Drug Evaluation and Research (CDER). At the July meeting of FDA's Manufacturing Subcommittee of the Advisory Committee on Pharmaceutical Science, Hussain and others outlined a number of steps FDA is taking to encourage more rational pharmaceutical development and manufacturing systems.

If a manufacturer can demonstrate a good understanding of key product attributes (e.g., stability, bioavailability) and provide evidence that it can control critical variables and detect product deviations, regulatory authorities will be able to review applications in one review cycle, permit improvements in a manufacturing process without prior approval, and implement a risk-based inspection process, explains Pfizer Vice-President John Berridge. To achieve this ideal situation, FDA is taking steps to re-engineer its chemistry, manufacturing, and controls (CMC) review process in new drug applications (NDAs) and abbreviated NDAs (ANDAs) for generic drugs. Prime goals are to curb multiple review cycles, reduce application resubmissions, and reduce oversight of most postapproval changes. At the same time, FDA is working with other regulatory authorities and manufacturers to reach agreement on new standards for submitting drug quality information in the common technical document (CTD) developed by the International Conference on Harmonization (ICH).

Streamlining CMC reviews

The current CMC review system is resource-intensive, imposes unnecessary regulatory burdens on industry, and discourages manufacturers from making improvements such as those achieved through process analytical technologies (PAT) in approved products, observed Moheb Nasr, director of CDER's Office of New Drug Chemistry (ONDC) in OPS. He cited a number of factors for this unfortunate state:

* ONDC reviewers evaluate all CMC information, regardless of its importance or the reviewer's expertise.

* Applications closely follow FDA and ICH guidances, even if a different manufacturing approach is more logical.

* ONDC does not examine manufacturing process information in detail because the current system leaves that task to FDA's field force.

* FDA and manufacturers seek tight product specifications determined by limited data to ensure consistency in a manufacturing process; this often leads to recalls and drug shortages.

* Manufacturers frequently submit late and voluminous CMC amendments, which delay reviews.

* NDAs seldom include critical information about pharmaceutical development which is necessary for a risk-based assessment of the product.

* CMC information in applications varies widely because many applicants fail to consult with FDA before filing an NDA, and fail to follow agency recommendations when sought.

These factors delay application approvals and discourage manufacturers from improving systems, adding to the cost of already expensive new drug products. A recent study found that manufacturing problems are responsible for delaying first-cycle NDA reviews of many new molecular entities. And with its workload rising, CDER is eager to eliminate unnecessary and redundant activities. This past year, ONDC reviewed 159 NDAs, 342 commercial investigational new drug applications (INDs), 1745 supplements, and more than 1000 annual reports.

A risk-based CMC review system, which is being developed first for conventional drugs, will focus on the relevance to safety and efficacy of critical quality attributes such as chemistry, formulation, manufacturing processes, dosage form, and product performance, Nasr explains. Interdisciplinary teams of chemists, pharmacists, engineers, and others using modern statistical methods to evaluate information in pharmaceutical development reports (PDRs) and a quality overall summary (QOS) will conduct reviews. The new approach aims to achieve more consistency among chemistry review teams and improve FDA's ability to oversee new technologies, combination products, and novel dosage forms.

FDA is implementing this more streamlined review approach first for CMC sections of resubmitted NDAs. Under a pilot study, a senior CMC reviewer will conduct a quick (14-day) preliminary assessment of a resubmission, order a copy of any referenced drug master file, and develop an "assessment protocol" for reaching approval. This information then will go to a primary reviewer who will perform an in-depth assessment and seek to resolve CMC issues quickly.

ONDC also is exploring ways to down-regulate or eliminate those CMC supplements unlikely to adversely affect the quality, purity, or stability of a drug product. A more efficient supplement review process would encourage continuous post-marketing product improvement by manufacturers and also free up ONDC resources for NDA reviews, Nasr comments. A related initiative is to encourage manufacturers to submit comparability protocols (CPs) in NDAs to link the current CMC policy to this new quality assessment approach. CPs also can facilitate continuous improvement by reducing the need to file manufacturing supplements when a firm wants to change a manufacturing process or product attribute.

Speeding up generics

Similar initiatives are being adopted by CDER's Office of Generic Drugs (OGD), which continues to struggle with an increasing number of ANDAs and supplements. OGD expects to receive nearly 600 ANDAs and more than 3500 supplements this year, noted OGD director Gary Buehler at the advisory committee meeting. On average, OGD takes 18 months to approve an ANDA because all applications must sit in a never-diminishing queue, with no preference allowed for very complete or very simple submissions that could be processed quickly. ANDA approvals also are delayed by legal disputes and lawsuits, which appear to be intensifying (see sidebar, "Generic drug debate accelerates").

Buehler would like more authority to identify applications suitable for quick review treatment and to review groups of applications for the same product. But because Congress must authorize such a change in the "first-in, first-reviewed" generic drug approval process, Buehler is trying to streamline the ANDA review system internally.

One initiative is to encourage manufacturers to calculate product specifications more carefully, which would reduce the time OGD staff must spend negotiating tighter limits. An OGD study found that 40% of all deficiencies in first cycle reviews relate to overly loose specifications, Buehler notes. He urges manufacturers to determine specifications on the basis of knowledge of the manufacturing process and critical product attributes and to provide a clear rationale for how specifications are selected.

This process, Buehler believes, will lead to more one-cycle reviews in initial applications and permit expedited handling of later supplements. Basing reviews on knowledge of the product and which manufacturing changes will make a difference represents "a fundamental change in thinking," Buehler says. The benefits for manufacturers are greater flexibility to improve manufacturing processes, more ease in making post-manufacturing changes, and fewer problems in plant inspections. Buehler is urging generics makers to demonstrate their expertise in drug product manufacturing by incorporating advances in pharmaceutical science and manufacturing technologies to improve product quality and reduce risk. Such an approach, he comments, will help generics makers challenge any perception that generic drugs are lower in quality than innovator products.

Harmonizing standards

In addition to streamlining its own CMC review process and data requirements, FDA is looking to gain international agreement on risk-based quality standards through the ICH. In the past year, regulators in the European Union (EU), Japan, and the United States agreed to develop new guidance encouraging manufacturers to provide information that reflects a better understanding of critical product and manufacturing design and process factors. The aim is to encourage risk-based approaches to manufacturing oversight and continuous improvement strategies in all global regions.