Biopharmaceutical Manufacturing: The Challenge of Global Regulatory Compliance - Pharmaceutical Technology

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Biopharmaceutical Manufacturing: The Challenge of Global Regulatory Compliance
This article provides an overview of regulatory issues facing companies that seek to market their biopharmaceutical agents globally, including a trend toward harmonization of requirements as well as the differences in rules concerning applications, GMP standards, and communication with reviewers.


Pharmaceutical Technology


Prepare for multiple inspections. Each regulatory agency conducts facility inspections independently and generally does not share information with its counterparts in other countries, although inspectorates are likely to examine the same areas and procedures. Differences in expectations and observations among each regulator's inspectorates, however, can complicate the review process somewhat. For example, a CMO undergoing inspections by FDA, EMEA, and MHLW will respond to each authority's observations and may refine a process or make changes to the facility to meet the requirements of one regulator. If any alterations are made, the CMO must then provide information about the change to the other agencies, explain the rationale, and may require regulatory agency approval.

Within the manufacturing facility, operators will find the inspection process to be quite different depending on the regulatory agency involved. Typically, FDA representatives will tour the facilities and request numerous documents to be brought to them, and European inspectors will spend a significant amount of time talking to operators and asking questions about processes. MHLW inspectors will examine the facility thoroughly, ask detailed questions, and take particular note of cleanliness and neatness. Before the inspection, the European and Japanese inspectorates will request a site master file, a source document that introduces them to the facility. As a result, the European and Japanese inspectorates are typically well prepared when they arrive, and their visits are highly structured.

The best way for a company to prepare for an inspection is to thoroughly understand the expectations of the visiting inspectorate and ensure the facility meets those expectations. To this end, it is important to have reliable contacts in the regulator's home country who can provide guidance before the inspection. For example, when preparing for a visit from regulators in Japan, Baxter walked through its Bloomington, Indiana, facility with representatives from its affiliates in that country to identify any special areas or items of concern on which the inspectorates could potentially focus.

It is also useful to perform a stop-gap analysis before the inspectorate's visit. A stop-gap analysis that uses US GMPs as a baseline may identify regulations concerning terminal sterilization and aseptic conditions that differ between the US and Japan. Awareness of these gaps enables a company to address any issues before the visit and prevent any unpleasant surprises during the inspection.

Verify suppliers' GMP compliance. International regulatory control over the testing and inspection of raw materials also has not been fully addressed by global harmonization efforts, even though joint guidelines for CGMP standards have been adopted by regulatory authorities in the US, Western Europe, and Japan. For example, stability testing requirements for APIs vary to some degree among the three major economic markets, raising the possibility that companies will have to perform multiple tests, a process that can be both time consuming and expensive.

Furthermore, ensuring API suppliers are CGMP compliant may involve various levels of responsibility on the part of the pharmaceutical company, depending on whether the pharmaceutical agent will be marketed in the US, Europe, or Japan. US regulatory authorities take the extra precaution of conducting preapproval, routine surveillance, and compliance inspections on all US and foreign manufacturing sites producing API for prescription medications to be sold in the US (9). FDA holds API manufacturers to the same current CGMP standards imposed on pharmaceutical product manufacturers, with API inspections covering laboratory operations, including evaluation of analytic methods, analytical data, laboratory procedures and instrumentation, analytic review of methods to establish impurity profiles, fermentation manufacturing processes, and multistep chemical synthesis processes (9). Upon inspection, FDA staff use process analytical technology to take continuous real-time measurements of quality attributes of raw and in-process materials and processes (10).

In 2005, the European Union issued guidelines requiring that all API for use in pharmaceuticals sold in Europe come from source companies compliant with CGMP standards. Both drug and API manufacturers must complete filings with European regulatory authorities, but current law does not obligate EU officials to inspect manufacturing sites. Overall, the drug company is responsible for ensuring that any APIs used in its products are produced in manufacturing plants that are GMP compliant. It is possible for API manufacturers to obtain certificates of quality through the European Directorate for the Quality of Medicines, and holders of such a certificate may be subject to inspections (11).

Communicating with regulatory reviewers

Ongoing access to regulatory agency personnel differs depending on whether a biopharmaceutical agency is working with FDA, EMEA, or MHLW. FDA reviewers and scientists are generally more accessible to companies than are their counterparts in Europe and Japan.

Typically, FDA reviewers are willing to provide pharmaceutical companies and CMOs with ongoing feedback and binding advice on potential improvements regarding applications for changes. Since 2004, when FDA presented its current philosophy concerning regulatory guidance for pharmaceutical manufacturing in "Pharmaceutical CGMPs for the 21st Century — A Risk Based Approach," the agency has sought to work with industry to continuously incorporate new scientific information into regulatory standards and policies (12). Consequently, a company wishing to change its process or facility may justify its approach and philosophy to FDA, and FDA scientists will consider a change in policy if they view this approach to be scientifically sound.

Conversely, access to EMEA reviewers is more limited and is complicated somewhat by the agency's organizational structure, given that EMEA's advice is not binding (13). The European Commission makes the final decision to approve or deny a marketing authorization application.

Meanwhile, the Japanese market has become much more open to Western industry in recent years. Japan modified its Pharmaceutical Affairs Law to open doors to non-Japanese organizations and allow pharmaceutical companies to outsource manufacturing operations. This move eases financial constraints on companies developing biologically based products (4). Despite greater openness by Japanese authorities, however, foreign companies looking to market pharmaceuticals in Japan will still benefit from having local partners, given that copies of regulations, and their respective translations, can be difficult to obtain.


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