Planning for Success

The pharmaceutical industry is evolving rapidly. More companies, scientists, engineers, and entrepreneurs are establishing contract manufacturing organizations, and developing new and generic drugs. They are searching for better or less expensive raw materials and finished products, and creating consulting and contract research organizations to service the global pharmaceutical industry.

In countries such as China, Poland, Korea, Vietnam, India, Turkey, Brazil and Iran, individuals are in the process of developing generic and new drugs and are submitting their first Abbreviated New Drug Applications (ANDA) to the US Food and Drug Administration (FDA). This is in the hope of receiving timely approvals and entering the lucrative US pharmaceutical market.

Although highly motivated and learning quickly, many of these individuals do not have sufficient experience in the pharmaceutical industry and are not entirely familiar with the requirements that are set by the US regulatory agencies.

On the other hand, in order to reduce costs or improve quality, many US companies are in search of partners in other countries to outsource the former's manufacturing, testing, or product development activities. These companies usually become frustrated by their inability to locate appropriate partners or may face difficulties during the transfer of technology.

This is perhaps to some degree due to the companies' own lack of resources, technical expertise, or motivation to manage activities overseas and ensure compliance. As a result, some organizations have abandoned the idea of outsourcing the development or manufacturing of new, legacy, or generic finished products after several attempts.



Understanding the Process
There is more to marketing pharmaceutical products in the US than just filing an ANDA. In the worst case scenario, some companies hastily decide on a product, produce some data and information, and mail several binders to the FDA. They then wait for the letter to arrive that announces the approval for their submission.

As a submission does not ensure approval, even a successful pre-approval inspection by FDA does not ensure a profitable outcome when it comes to marketing a generic drug. Success requires determining and focusing on the right opportunities, utilizing the right people and tools, and doing the right thing.

For companies in developing countries and for startups or even established firms in the US and Europe, choosing the right generic product to develop and manufacture would determine the future success and sustainability of the company.

There are examples of organizations that have set up operations in the US or overseas that have begun to develop half a dozen generic drugs in parallel - only to eventually confront technical difficulties with difficult-toformulate drugs, a lack of sales and customers, or price pressures from competitors - after receiving the necessary regulatory approvals.



When deciding on which generic drugs to develop and market, it is important to ensure that a market analysis is performed, the sales and distribution channels for the specific drug category have been determined, and potential customers have been established. It is critical to complete a thorough technical due diligence of the product to be developed. It is also necessary conduct a realistic gap analysis between the requirements to formulate or manufacture the product versus the company's or contract organization's true technical and manufacturing capabilities.

In addition, it is vital to keep in mind that innovator companies can sometimes utilize different "anti-generic" strategies to keep away potential generic drug manufacturers. These strategies could include:

• The launching of authorized generics
• Creating a secure innovator-buyer relationship before the patents have expired
• Developing a strong portfolio in the product category
• Submitting citizen petitions to the FDA
• "Ever-greening" the drug by modifying the existing product such as launching extended release versions

The generics industry can be profitable if suitable products are chosen to be developed and marketed, the compliance requirements are met, customers are established, and the price is right. Selecting the right generic drug to make and sell, and anticipating the technical, compliance, legal, and regulatory hurdles, is the first and perhaps the most critical step in establishing or maintaining a successful organization.



Quality Emphasis
Quality should be built into the product and testing alone cannot be relied upon to ensure product quality. As the "FDA Guidance for Industry Quality Systems Approach to Pharmaceutical current Good Manufacturing Practices (cGMP) Regulations" indicates, the key concepts that are critical to the pharmaceutical quality system are:

1. Quality
2. Quality by Design and Product Development
3. Quality Risk Management
4. Corrective Action and Preventive Action (CAPA)
5. Change Control
6. The Quality Unit
7. Inspection Model

Unfortunately in many instances, there has been a lack of understanding of what it takes to build a robust quality system within manufacturing and testing organizations both in and outside the US. In some cases, organizations are under the delusion that simply having a large number of Standard Operating Procedures (SOPs) for all the different tasks is sufficient to ensure the quality of products.

In certain facilities, the number of SOPs that are needed to manufacture and support one product exceeds several hundred. This makes it almost impossible to train personnel, manage document control activities, or comply with such a large number of documents in any meaningful fashion.

These organizations have ignored the fact that the purpose of implementing a quality systems approach is to enable manufacturers to efficiently and effectively validate, perform, and monitor operations, and to ensure that the controls are scientifically sound and appropriate. A quality system is one example where more may not necessarily be better.

For these organizations to be able to ensure product and facility approval by the FDA and a continuous supply of compliant products, quality must be built into every aspect from facility design and construction to equipment selection and qualification, process validation, manufacturing and testing, and all day-to-day operations.

During the past couple of decades, a large portion of US drug manufacturing capabilities have vanished and more pharmaceutical products, which are destined for the US market are being manufactured overseas. In many countries around the world, companies and entrepreneurs are constructing new facilities or are revamping and modifying existing ones to meet US FDA requirements. In many instances, these efforts fall short.

When first embarking on a new pharmaceutical facility, consideration will need to be made as to what cGMP requirements will apply to the project and how they will impact the project lifecycle. These may differ based on many variables but there are common general requirements that cover all the cGMPs worldwide.

Based on an assessment of the regulatory requirements for the type of product and where it will eventually be marketed, the engineering group must first begin to define the GMP requirements for the facility. Generally, issues and areas that are to be considered during the design phase will include:

1. Products, processes, and equipment
2. Location and facility layout including environment and containment strategy
3. Automation and level of technology
4. Equipment selection
5. Material and people flow
6. Regulatory requirements
7. Validation strategy

These basic requirements can then be refined for the various aspects of the project to allow the facility to be engineered properly, adequately, and in a compliant fashion.

Constructing and validating a pharmaceutical facility is a complex task and requires project management skills, technical oversight, and daily attention to details - in order for the company's technical and manufacturing staff to eventually take over a facility that can produce a compliant product at the required volumes.

Many believe that developing a generic drug is simply reviewing the innovator product's label and formulating the generic version using the same Active Pharmaceutical Ingredients (API) and excipients. Unfortunately this is far from reality. Different dosage forms present different challenges both in formulation and process development. Although perhaps the formulation and the scale up of a true solution is in most cases straight forward, scientists and engineers could face difficulties with certain solid dose products, creams and ointments, or suspensions.

Quality by design means developing a product and a manufacturing process that will ensure that the product consistently attains a predefined quality at the end of the manufacturing process. This should be applied from the onset.

In addition, quality by design, in conjunction with a robust quality system, would provide a framework for the transfer of product knowledge and process understanding from drug development to the commercial manufacturing processes.

Validation
As more facilities are built overseas and an increasing number of activities are outsourced, most of the facility and equipment qualification and validation tasks are entrusted to the equipment vendors or third-party contractors. Partly due to repeated layoffs and organizational restructuring, many US companies today do not have the resources to perform these tasks on their own. The same issue and perhaps in a more severe form applies to startup companies.

In most cases, the vendors and independent contractors are experts in what they do and at least in theory can deliver service and compliant qualification and validation documents. However, this can only be achieved if the right vendors are chosen. A comprehensive user requirement document needs to be developed at the beginning of the project and in collaboration with the vendors.

Also, simply relying on the vendors and contractors to perform the qualification and to produce the compliant documents is risky and is in violation of cGMP requirements. Every qualification and validation protocol and report, and every deviation must be reviewed and approved by qualified internal personnel before they are accepted.

In addition, it is important to remember that in accordance with the quality systems approach, validation is not a one-time event, but an activity that must continue throughout the life of a product. Therefore, as experience is gained in commercial production, opportunities for process improvements may become evident. The organization's internal personnel can eventually capitalize on these opportunities.

Many first time applicants underestimate the time that it takes to prepare and submit a well designed and well executed ANDA. When it comes to generics, a major portion of the regulatory submission is taken up by the Chemistry and Manufacturing Control (CMC) documents. To ensure process efficiency, it is important to first agree upon and develop a list of activities and documents that are needed to be submitted to the FDA and then assign responsibilities and timelines to each task.

Regulatory affairs professionals can usually develop a detailed template of the submission based on FDA expectations beforehand. This will become useful in organizing the documents that need to be filed.

All of the documents that are to be filed must first be reviewed and approved by appropriate departments - typically product development, technical services, and quality. The worst that could happen to a submission is when incorrect information or failed results are filed. This situation can easily be avoided by a thorough review of documents by trained and experienced personnel before the former are forwarded to regulatory affairs.

It is helpful to be mindful that for most products, the manufacturing of stability batches and the conducting of stability studies are usually the rate limiting step before filing a regulatory submission.

Therefore, in order to shorten the time that is takes to perform all the necessary tasks and at the same time to ensure the quality of the regulatory submission, it would be wise to organize all other tasks around these two activities.

Pre-Approval Inspection
Pre-Approval Inspections (PAI) are a prerequisite to launching an NDA or ANDA product in the US, and are an essential element in the FDA approval process. There are primarily three reasons for FDA's PAI:

1. Verify the manufacturer's compliance with cGMP
2. Verify the accuracy and completeness of the manufacturing related information that has been submitted in the ANDA
3. Evaluate the manufacturing control for the pre-approval batches upon which the ANDA approval is based

Before and during the PAI of a facility, the primary goal of site management should be to manage the inspection effectively. This means to completely understand FDA expectations and to communicate them to all personnel, prepare the site, organize and provide the documents and information that are requested as proof of evidence of compliance, and interact appropriately with the inspectors.

The FDA's Drug Manufacturing Inspection Compliance Program, which contains instructions to FDA personnel for conducting inspections, is a systems-based approach to inspection and is consistent with the agency's quality system model. During a PAI, one should expect to be asked questions that are related to any areas that affect the product for which the inspection is taking place.

The FDA inspection team normally includes a lead investigator and depending on the type of product, could comprise of a microbiologist, a chemist, or personnel from any other discipline. Depending on the product category and the inspectors' backgrounds, the areas that are addressed during an inspection could vary to some degree. However, questions regarding the handling of failures and deviations, out of specification results, operator training, facility qualification, material segregation, and vendor audits should always be expected.

Pre-approval inspections are typically challenging. At best, they disrupt daily operations while in the worst case scenario, could result in a loss of revenue and damage the company's reputation. However, one should not be overly concerned if the facility that is to be inspected, has been designed and constructed with cGMP guidelines for the particular product; if the personnel are appropriately trained and the training is fully documented; and if the quality systems are in place.



Post Approval Activities
Upon the completion of a pre-approval inspection and the approval of the ANDA, the generic drug manufacturer can usually start marketing the product in the US. However, manufacturing a pharmaceutical drug is a responsibility that requires constant diligence, communication, and the continuous monitoring of the manufacturing and quality aspects of the drug. In addition, it is necessary to conduct the trending of the data that is obtained from the facility, manufacturing process and customers.

Post drug approval is also an important part of FDA's area of focus. The goal of these activities is to monitor the ongoing safety of marketed drugs. This is accomplished by reassessing drug risks, based on new data that is obtained after the drug has been marketed, and recommending ways of appropriately managing that risk.

A vital part of FDA's mission is to monitor the safety and effectiveness of drugs that are currently available to the American people. To meet this goal, it has in place, post-marketing programs that monitor marketed human medical products for unexpected adverse events. These programs alert the agency to potential threats to public health. Manufacturers of prescription medical products are required by regulation to submit periodic adverse event reports to the FDA.

After a drug is approved and marketed, the FDA uses different mechanisms such as Pharmaceutical Industry Surveillance to ensure that firms adhere to the terms and conditions of approval that have been described in the application, and that the drug is manufactured in a consistent and controlled manner. This is performed by periodic, unannounced inspections of drug production and control facilities by the agency's field investigators and analysts.

Selecting, developing, manufacturing, and marketing generic drugs can be financially rewarding. However, it is also a complex and sometimes expensive process with many pitfalls, if it is not carried out correctly. In every step of the process, beginning from facility design to the manufacturing of every batch upon approval of the ANDA, cGMP requirements for the facility and the quality of the finished product must be adhered to, to ensure the approval and continuous supply of compliant and efficacious drugs.