Pre-Approval Inspections (PAI) have become a prerequisite to launch an NDA or ANDA product in the U.S. The origin of this inspection can be traced back to generic drug industry scandals in the late 1980s. At that time, one could make bench scale batches of a product and submit the application for approval. It was only after approval that companies customarily started to develop the process for production. Purchasing, installing and qualifying the equipment was considered only after the approval of the product. From a business standpoint, this made perfect sense.
One of the flaws of that system was that process scale up, as well as the changes that were normally required to be made during the development and scale-up effort, did not reflect what was submitted to the FDA as the process that would be used commercially. With the implementation of PAI, some companies proceeded to set up plants to manufacture their products commercially, only to find out several years later that the drug did not get approval from the FDA. The concept of process validation, although part of regulations from the beginning, was brought to the forefront. When one examines the statistics of recalls, lack of validation is one of the main reasons why products do not conform from batch to batch. Usually, the robustness of the process was not investigated before the marketing of the product.
The initial impact of the PAI requirement from FDA was confusion. Several companies failed to pass this new requirement from the agency. Table 1 (p. 48 of the magazine) illustrates the recent enforcement trends. In 1997, the FDA issued 1,140 warning letters, the majority for medical devices (369), drug violations (266), food and cosmetics (220), animal drugs and feeds (148) and biologicals (68). The FDA's volume of enforcement actions decreased in the mid-1990s; however, these changes likely do not reflect any shift in the FDA's emphasis on rigorous enforcement. Rather, the declines may be due to several independent factors, including: "leveling off" from record levels of court actions in 1992; a concentration on larger, landmark cases; and, in some areas, the effects of new organizational structures and reduced Resources within the agency. The implementation of PAIs for new drugs may also be one of the contributing factors in the reduction of prosecutions over the years.
The 1998 PAI data shows facilities abroad outperforming U.S. plants. These favorable foreign PAI results parallel FDA's enforcement data for fiscal year 1998, which shows a significant reduction in the number of warning letters issued to overseas plants. This improved compliance record reflects a concerted effort by the agency over the past few years to bring foreign Active Pharmaceutical Ingredient (API) manufacturers into compliance through increased enforcement oversight and better GMP guidance. During 1998, FDA's field organization conducted 1,016 inspections. The types of plants covered included contract laboratories, packagers and manufacturers as well as bulk and finished dosage manufacturers.
Table 2 (see p. 50 in magazine) provides a summary of the field pre-approval recommendations with or without inspections and Table 3 (see p. 52 in magazine) shows the issues implicated in "withhold" recommendations for both NDAs and ANDAs.
There is a move within FDA and in industry to form GMP compliance partnerships. FDA has already opted to perform fewer pre-approval inspections in light of the industry's im-proving compliance track record. The First-Party Audit program provides for drug firms with solid track records of GMP compliance to submit internal audit findings to the FDA in lieu of routine agency on-site inspections. FDA's district offices are encouraging firms to initiate a dialogue about the production of new chemical entities, manufacturing changes and construction of new facilities before application and supplements are filed with the center, in order to avoid major GMP problems later on.
"Plant-not-ready" has been the primary reason for withholding recommendations during the past several years despite FDA's efforts to warn firms that the time between the actual filing of an application or supplement and the scheduling of the PAI has been reduced.
The general assumption one should go with is, "Do not file an application unless you are willing to face an immediate PAI." The contract manufacturing organization (CMO) provides the "risk-free" alternative to solve this dilemma.
Contract Manufacturing Facility and PAI
Pharmaceutical firms are well aware of specific areas of activity that are either non-core to the ongoing strategy or are not economically viable to retain in-house. This is why there has been a significant growth in outsourcing. The outsourcing strategy allows pharmaceutical companies to convert fixed costs to variable costs. The potential for increased revenue and cost savings is driving the use of contract manufacturing.
Contract manufacturing organizations have the advantage of possessing the facility, systems, technology and personnel to offer to the prospective client. FDA requires the industry to provide evidence that the firm knows what it is making and knows how to make it. As has been seen time and again, the first objective of the PAI program is to assure that the facilities listed in the application have the capabilities to manufacture, process, package and provide adequate analytical controls according to the cGMPs.
The presence of an outsourcing organization in a product launch plan offers several advantages to a pharmaceutical company. The outsourcing facility will be able to provide a functioning cGMP compliant facility and will be capable of providing necessary equipment, trained personnel and know-how that may not be available in the pharmaceutical company.
Pharmaceutical companies must address the concern over loss of control to the outsourcing organization, as process know-how and in-house expertise become the province of the CMO. However, the benefits of outsourcing outweigh these downside considerations. For a NDA product, product launch timing and business considerations may cause a company to consider a qualified CMO. An ANDA product or existing product may also be outsourced, in order to free up in-house capacity for a new product.
The major pharmaceutical companies are strategically deciding at the early stage of a product's life cycle whether the product will be outsourced, even though the long-range goal is to bring the product in-house. Sponsors can start working with the outsourcing organization from the early stages. Phase I through Phase III trials could last anywhere from three to five years. This provides the sponsor company with time to evaluate the outsourcing organization. The quality of the programs, personnel, facility, technical expertise and the general business attitudes can all be evaluated during this period. Thorough knowledge of the outsourcing organization and its business ethics and history of compliance may assure the drug company that, if the facility is incorporated into the NDA or ANDA filing, the prospect of passing a PAI are very high. The drug company can help the outsourcing organization bring itself into compliance.
Sponsors seem to believe that it is easy to demand that CMOs demonstrate a higher level of compliance than the sponsor's own company. In fact, sponsors are at an advantage when it comes to CMO compliance, because their auditing team, along with an independent auditing organization, can audit the contract manufacturer until such time that they feel the PAI will be successful.
Generally, one should assume that the FDA will review the following during an inspection:
a. Facility and systems validation document (water system, HVAC, etc.).
b. Clinical batch records, stability protocols, stability data and analytical methods against the regulatory submission. This data may or may not be at one location. Some drug companies will carry out the analytical controls in their own facility. If there is more than one facility involved, such as API manufacturing, analytical laboratory, manufacturing or packaging, different PAIs must take place.
c. All analytical laboratories that generated data included in the submission.
d. The batch records for stability lots, biobatch lots for manufacturing of the bulk, new drug dosage form (The process validation data is not required for U.S. PAI. However, before marketing the product, the complete process validation data is reviewed by the FDA in an additional inspection.).
e. The validation protocols; i.e., cleaning, computer and methods validation.
f. Development report.
g. Equipment installation and operational qualification data for each piece of equipment in the submission.
h. Validation data for any reprocessing filed in the submission.
i. Sufficient stability data to support the expiration date.
j. Change control.
l. Control of documents.
m. Standard Operating Procedures (SOPs), from receipt of raw material to warehouse distribution.
Regulatory and legal issues are also involved when a drug company uses a CMO. The CMO must comply with cGMPs. Also, the drug company must consider the CMO as an integral part of the drug application and must include the same information for the contractor's facilities that it does for its own. The CMO shares responsibility for following all the steps necessary for gaining approval for the application.
The PAI of a CMO facility is a true partnering of resources. The drug company brings the knowledge of the product, analytical methods and performance characteristics of the resultant manufactured product, while the contract manufacturer brings the facility, personnel, technical know-how, equipment and experience of manufacturing under the cGMP.
However, since the potential success of the product in the marketplace is based upon gaining approval from FDA at the contract manufacturing site, it is imperative that drug companies work with a reputable organization. Generally, it can take two to three years between the submission following PAI and the approval to manufacture commercially. The drug company needs assurances from the contract manufacturer that the capacity will be available when the product is approved. This poses a serious financial strain on the contract manufacturer who has the investment of the plant, equipment and infrastructure, while the drug company does not have to bear these costs. Recognizing this fact, drug companies and contract manufacturers are considering a mutually agreeable compensation for keeping the manufacturing capacity available while waiting for FDA approval. The nature of this compensation could be a reservation fee that covers the fixed costs for that product at the manufacturing site.
PAI of Contract Manufacture of API
The FDA's scrutiny of API manufacturers has been increasing. The biggest issue is facility flaws that can cause product contamination. Most of these chemical facilities were never constructed with GMPs in mind. As a result, common design criteria used for finished dosage form manufacture (such as flow of material from receipt through production, flow of personnel, pressurization of areas so that no cross-contamination can occur) are never considered. Other concerns during the PAI are the water system, poor documentation regarding the equipment qualifications, technology transfer, change control, SOPs and good laboratory practices. As FDA is gradually applying GMPs to the upstream processing of pharmaceuticals, API manufacturing facilities will be required to comply with the same guidelines that the dosage form manufacturers are judged by during the PAI. Therefore, the same consideration should be given in selecting a cGMP compliant contract API manufacturer as one would select the finished dosage form contract manufacturer.
PAI of CMOs in a Foreign Country
The PAI of foreign pharmaceutical facilities are generally product specific. In 1996, the initial "withhold recommendation" rate for foreign firms was 42% versus 18% for domestic firms. However, in 1998, the foreign pharmaceutical facilities fared significantly better (9%) than domestic facilities (20%). There is now a better understanding of GMPs in foreign countries. The availability of consultants and organizations expressly catering to foreign pharmaceutical plants has increased the possibility of passing PAI successfully. The requirements for foreign PAIs are much the same as the domestic ones. Several of these foreign establishments are suppliers of the API. In 1995-96, API firms received about 74% of all the GMP compliance letters that FDA sent to foreign firms. Overall, finished product formulators fared better than API manufacturers during 1995 and 1996; 11% of inspections resulted in noncompliance letters compared with 17% of API inspections. Of all the foreign inspections conducted by FDA in 1996, approximately 90% (258) were PAI, compared to 429 domestic PAIs. Nearly one-half of the warning letters sent to foreign bulk chemical manufacturers during 1996 cited problems with the firm's stability testing program, which included sample storage, evaluation procedures, number of batches tested, control of labeling and type, amount of supporting data, retesting and out of specification (OOS) results investigations.
Worldwide, pharmaceutical companies are struggling with the competing priorities of lowering costs, rising customer expectations, ever-increasing regulatory burden, and the need to reduce cycle times and minimize time-to-market. Pre-approval inspection of a contract manufacturing facility is a partnering of resources. The synergies of two partners can result in a successful PAI. Irrespective of the contract manufacturer's lo-cation (whether domestic or foreign) and scope of operation (whether finished pharmaceutical or API) the same issues of GMP compliance must be addressed in preparation for PAI.