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The author provides an overview of key regulatory issues facing companies seeking to market their biopharmaceutical agents globally.
In recent years, biopharmaceutical companies have joined Big Pharma in expanding their businesses into global markets. In the process, many of these companies have found that navigating disparate regulatory requirements can be confusing, time consuming, and risky. A lack of understanding about a particular regulatory agency's requirements for processes or facilities can lead to excessive delays in market authorization, thereby affecting a product's opportunity for success in a highly competitive market.
Nonetheless, regulatory agencies from the United States, Europe, and Japan are making visible efforts to collaborate and coordinate their requirements for processes and manufacturing facilities. This harmonization of rules means the process of global regulatory compliance has become somewhat easier than it was just five years ago. The adoption of unified guidelines as well as increased collaboration with industry in major economic markets have eliminated many duplicative and dissimilar testing requirements for manufacturers.
Even so, key differences in the regulatory review process require that pharmaceutical companies seeking to market products in several countries take a truly global approach to regulatory issues, build a strong working knowledge of the countries and their regulators, and adequately prepare for the rigorous process of submitting applications and undergoing regulatory review.
Moving toward harmonized regulatory requirements
The process of harmonizing global regulatory requirements began more than 15 years ago, when industry groups and regulatory authorities in the US, Western Europe, and Japan formed the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). This industry–regulatory consortium seeks to accelerate global development of new medicines as well as decrease research and development costs by eliminating duplicative or contradictory requirements among various regulators while maintaining standards on quality, safety, and efficacy. The rationale for ICH is that more efficient use of research time and money could make life-saving medications available to consumers more quickly and reduce overall healthcare costs (1).
Through ICH, regulators and industry experts discuss scientific and technical aspects of the development and manufacture of medicinal products and agree on scientific and quality standards for clinical, laboratory, and manufacturing practices. Between 1990 and 2004, six ICH conferences were held, leading to the release of dozens of technical guidelines, common vocabularies, and specifications for a common marketing authorization application (2).
The US Food and Drug Administration, European Medicines Agency (EMEA), and Japanese Ministry of Health, Labor, and Welfare (MHLW) now rely on ICH technical guidelines when ensuring pharmaceutical companies comply with quality standards.
But complete harmonization cannot happen overnight, or even within 15 years. Differences in governmental structures, cultural norms, and business environments lead to distinct interpretations in and implementation of international guidelines. In addition, there is often a lag between the publication of ICH guidelines and the adoption by individual countries because of the time it can take for each governmental body to put the change through its own review and approval process.
Consequently, regional differences still exist in how individual countries go about ensuring compliance with current good manufacturing practices (CGMPs), and those distinctions can influence costs and the speed with which a company obtains marketing approval. Differences in regulatory requirements can be complex and affect nearly every aspect of the marketing authorization process.
Submitting new drug applications to multiple regulatory agencies
Despite increased coordination among FDA, EMEA, and MHLW in recent years, differences in each agency's submission requirements warrant that companies closely monitor all three agencies for changing rules and requirements, particularly concerning the information that must be included as part of the submission and the need for local partners. For small biopharmaceutical companies, submitting multiple new drug applications while simultaneously seeking to expand business overseas can be an overwhelming task to handle alone.
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.
Ensuring global GMP compliance
To ensure compliance with regulatory authorities, pharmaceutical manufacturers must meet CGMP standards for quality and sterility, but the nature of these standards can be open to differing interpretations depending on the regulatory authority involved. Companies will find that regulators don't always agree on what constitutes an acceptable process validation or even how to define aseptic conditions. EMEA, for example, requires clear separation parameters for aseptic and nonaseptic materials that are much more restrictive than those of the other two regulatory bodies.
As a consequence, a CMO or manufacturer looking to maintain global regulatory compliance for its manufacturing operations will incorporate the most stringent requirement of all the regulators into its manufacturing process. Therefore, designing a facility that meets FDA, EMEA, and MHLW requirements is a complicated, expensive process, but it is absolutely necessary in a global economy.
To this end, companies should be aware of differences among regulators in terms of GMP standards for validation of procedures and equipment, facility inspections, and evaluation of raw materials. Knowledge of current GMP trends within the industry and regulatory agencies is also a must.
Be prepared to complete validation before European clinical trials. To obtain regulatory clearance, a pharmaceutical company must validate every step in manufacturing, including formulation, fill, and finishing, to verify that every process and machine consistently does what it is supposed to do. For companies developing new biopharmaceutical agents, validation is a tedious process because it can be difficult to determine a robust, repetitive, and reliable process for manufacturing biologically based APIs.
FDA and EMEA differ concerning the point in a product's development at which the validation of processes and facilities must be finalized. The EU requires biopharmaceutical manufacturers to complete process development and have processes and facilities fully validated for GMP before agents are used in early-stage clinical trials (7). This rule means that European requirements for investigational products are closely aligned with those of commercial products.
Although US rules concerning GMPs are generally in accord with those of Europe, FDA gives academic researchers, manufacturers, and CMOs some latitude when producing small batches of experimental drugs by assuming that phase-appropriate CGMP compliance will be used and controls will develop with the process and product through clinical development. FDA rules for investigational new drug applications, therefore, are intended to encourage early-stage biopharmaceutical research (8). As a result, regulatory guidelines in the US protect the safety of clinical-trial subjects but also enable biopharmaceutical producers to test more products in early-stage clinical trials before investing in processes and facilities that are fully validated and compliant.
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.
Given the differences in requirements and expectations among US, European, and Japanese regulators, companies must take a global approach to regulatory compliance issues. For companies looking to expand globally, success often requires building strong working relationships with manufacturing partners that possesses the right degree of vigilance, communication and focus on quality. Following are three golden rules that generally help to smooth the marketing authorization process.
Never take compliance for granted. Differing interpretations of simple international guidelines can hinder the approval process. Therefore, it's critical for biopharmaceutical companies to either build expertise in global regulatory affairs or partner with a CMO that has a strong audit history with regulators in the US, Europe, and Japan. Working with a regulatory group that has the capacity to monitor multiple global entities enables a company to remain apprised of any regulatory changes that can affect their products.
At a minimum, smaller biotechnology operations should consider a CMO's familiarity with global regulatory issues. 0thorities can minimize the potential for costly production delays. An experienced facility will be able to smoothly implement processes and procedures that satisfy the needs of multiple international agencies.
Communicate regularly. When a regulatory group works collaboratively with the technical experts in a manufacturing operation, required facility or procedure changes are likely to be completed smoothly and effectively. As a consequence, it's important for biopharmaceutical companies to consider communication practices when building their regulatory capacity, either internally or with a CMO. Regulatory groups need to communicate consistently with the entire manufacturing organization, including technical services, quality groups, and laboratory personnel. Everyone involved in the manufacturing operation not only should understand the changes that are being required, but also should grasp the rationale behind them.
Strive for quality. It's possible, when dealing with multiple regulatory groups, to lose sight of the ultimate goal of ensuring patients get the drugs that give them the best opportunity for treatment. Having a tunnel-vision approach toward GMP standards, in which changes are made only for the sake of compliance, places a company at risk for delaying marketing availability of a product that could potentially save lives.
When working with a CMO, biopharmaceutical companies need to consider the manufacturer's overall approach to quality, rather than just its history of GMP compliance. It's important for companies and their CMOs to understand and appreciate the unwritten expectations behind these requirements. By working on the front end of the development process to ensure facilities, procedures, and products are of the highest quality, companies will be much more effective in getting vital drugs to the patients that need them.
Kelly Davis is the senior manager of regulatory affairs at Baxter Pharmaceutical Solutions (Bloomington, IN), tel. 812.333.0887, fax 812.332.3079, Kelly_Davis@baxter.com
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