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


Understand the regulator's rules and tailor the data submission accordingly. Submitting applications for investigational drugs or new drug marketing authorization in multiple countries can be a cumbersome process, involving various fees, schedules, and review timelines. Although FDA, EMEA, and MHLW applications now follow a similar format, each authority requires the inclusion of different types of data. FDA, for example, requires extensive information about facilities and validation processes, in addition to clinical trial data, to be included in a new drug application (NDA). EMEA asks for less validation data, relying instead on inspections to gather this information.

Another point of distinction among regulators in the US, Europe, and Japan concerns the requirement to include data on materials, procedures, or validated equipment within the application. In the US, FDA allows organizations to submit and maintain drug master files (DMFs) covering manufacturing facilities, operating procedures, active pharmaceutical ingredients (APIs), packaging materials, delivery devices and excipients or other additives (3). DMFs allow a company to maintain data in a centralized location for reference by a multitude of applications. Through each application review and approval process, the DMF data are reviewed, which provides an additional level of compliance confidence. This can also ease the application burden somewhat. For example, when a company hires a contract manufacturing organization (CMO) and uses the CMO's proprietary technology, the application only must reference the relevant DMF rather than include extensive data on the materials, process, or validated equipment within the application.

Japan has made changes to its Pharmaceuticals Affairs Law in recent years to allow DMFs for raw materials, including APIs, excipients, and other additives, which can be filed separately from the submission package (4). This change eases regulatory review in that country and enables CMOs to keep confidential data concerning raw ingredients, which once had to be included with the entire new drug application package.

Conversely, EMEA accepts DMFs for active substances, mainly vaccines, as part of its marketing authorization process (5). As a consequence, much more information about processes and products must be included in the EMEA application because companies submitting applications cannot use existing data on matters such as closure systems, stability, or expiration dating. This requires the company or the contract manufacturing organization to collect new data for each application.

As a result, if a company is marketing a lyophilized product that must be reconstituted at the point of use, the marketing application in Europe would need to include detailed product-specific information on the product and the diluent, as well as the container that holds them both. For the same product, the US application could reference existing DMFs for the diluent and the container.

DMFs provide a central data storage location and save time during amendment generation. With a US DMF, only one amendment must be written and subsequently referenced by various applications. However, each European Union application must be amended individually, which adds cost and time.

Form reliable partnerships. Another hurdle for small businesses is the identification of partner companies within the region where marketing authorization is being sought. Ensuring that partners are reliable and informed is critical for several reasons.

First, regulatory authorities often require it. A US company submitting an application to the EU will need to provide EMEA with the name of a qualified European expert (i.e., qualified person) to release the pharmaceutical product destined for the EU market. In compliance with the regulations, the qualified person must reside within an EU state.

In Japan, applicants must identify a local market authorization holder (MAH), the entity that will actually receive the license for manufacturing and marketing. The MAH must guarantee the safety, quality, and efficacy of the product and comply with good quality practices, GMPs, and good vigilance practices, which monitor postmarket sales (6).

Beyond regulatory requirements, a second reason for having an informed local partner is to overcome language barriers and better understand local requirements and interpretation of regulations.

Reliable, informed partnerships are particularly beneficial for outside companies seeking to enter markets in Asia and the Pacific Rim. In those areas, partners can help the company navigate around some of the regulatory landmines and streamline the application process in several ways, including explaining any unwritten expectations of local regulators about how documents should look or how particular explanations should be phrased.

Partners also can explain aspects of the regulations, the agency, or the business culture that are foreign to the home country. Confidentiality of a company's application is one example of where FDA and some Asian regulators may differ. For example, assume a CMO has two clients whose products are manufactured in similar ways and who have submitted applications to market their agents in Taiwan. Client A has received marketing approval in Taiwan, while Client B's application is pending. The regulatory authority in Taiwan notices that some information about the manufacturing process is missing from Client B's application and asks the CMO, through its local partner, for permission to lift this information from Client A's documents.

The first instinct of a US-based CMO would be to refuse, because the confidentiality of each company's regulatory application is the standard practice in the US. The local partner, however, will explain that contents of particular regulatory applications are not necessarily confidential in Taiwan, so insisting on secrecy would be pointless, because information in the application is already known by the regulator as well as other local companies.


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