REGULATORY REQUIREMENTS

2. REGULATORY REQUIREMENTS

2.1. Drug/Device Development and Application for Approval

Whether a manufacturer intends to market products world- wide or only within the United States, numerous regulations must be satisfied before market entry is permitted. These regulations have been established to protect the public safety. Generally, these regulations focus on assuring that the inten- ded drug or device has the safety, identity, strength, quality, and purity (drugs) it purports to have and that devices are safe and effective for their intended use. Requirements for the applications of new drugs and devices can be voluminous and complicated. Regulatory requirements vary depending on the clinical indication and mode of use. To improve the timeliness of the product development and regulatory approval processes, a basic understanding of regulatory requirements is recommended.

2.2. International Considerations Major new products are being considered for global markets

as well as US domestic markets. To sell products abroad, there is usually a product approval or registration process for market entry. Understanding international quality and regulatory standards and requirements can improve speed- to-market and reduce frustration among the professionals responsible for new product approval. These requirements usually come from the country’s regulatory body responsible for assuring the safety of the product. A few of these key regu- latory bodies are noted in Table 1 .

Unfortunately, there is little standardization of product approval requirements by the major regulatory bodies of the world. There are, however, harmonization efforts underway with most major regulatory bodies participating. The Interna- tional Conference on Harmonization (ICH) has made signifi- cant progress in setting global specifications. The intent of these global specifications is that eventually all re- gulatory bodies, worldwide, will recognize and apply these specifications consistently. The ICH has published guidelines

Quality and Regulatory Considerations 585 Table 1 Regulatory Agencies by Country

Country Regulatory agency United States

Food and Drug Administration United Kingdom

Medicines and Healthcare products Regulatory Agency (MHRA) Japan

Koseishio

Canada Health Protections Branch France

Agence du me´dicament Germany

Bundesinstitut fu¨r Arzneimittel und Medizinprodukte (BfArM) and the Paul Ehrlich Institut

Italy Istituto Superiore di Sanita` Spain

Ministerio de Sanidad y Consumo

in the areas of quality, safety, and efficacy (see Appendix 1 ). These guidelines provide an excellent reference for any indivi- dual or organization involved in pharmaceutical product development. The hoped for advantage of regulatory harmoni- zation will be the development of mutual agreements between and among regulatory bodies. These agreements will allow one country to accept the drug and device application already approved by other countries.

2.3. Current Good Manufacturing Practices In the United States, the Food and Drug Administration

(FDA) has been given significant regulatory power under the Food, Drug and Cosmetic Act. This Act is enforceable, under Federal power, and contains key terms such as adul- teration and misbranding. Good Manufacturing Practices were developed to establish FDA’s expectations on how drug and device manufacturers should comply with the Food, Drug and Cosmetic Act. These regulations can be found in the Code of Federal Regulations as follows:

Title 21 Code of Federal Regulations Part 211 (Drugs) Title 21 Code of Federal Regulations Part 820 (Devices)

These regulations provide the minimum acceptable requirements for manufacturing drug and device products.

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Failure to comply with these regulations constitutes adultera- tion under the Food Drug and Cosmetic Act. Once a product is deemed adulterated the product or products involved may be recalled or seized. Manufacturers can be enjoined and long court battles can result. While the movement towards regula- tory harmonization advances, the FDA continues to operate under its own set of rules. Exemplified by the sheer number of detailed regulations coupled with the frequency and inten- sity of regulatory actions, the FDA is considered the world’s premier regulatory body. The FDA has published many useful guidance documents on the development and manufacturing of drug and device products. FDA guidance documents repre- sent this Agency’s current thinking on a particular subject. According to the FDA they do not create or confer any rights for or on any person and do not operate to bind the FDA or the public. The FDA will accept alternative approaches, if such approaches satisfy the requirements of the applicable statute, regulations, or both. These guidelines are particu- larly useful since they elaborate FDA expectations and direct enforcement activity. Additionally, they have been found use- ful in the development community when scientists are actively involved in the development or modification of drug and device products.

Guidance documents cover key topics such as advertising,

biopharmaceutics, chemistry guidances, clinical guidances, compliance guidances, generic drug guidances, information technology guidances, and labeling guidances.

Other guidance documents come in the form of FDA investigator inspectional guides. These guides provide the

* FDA guidance documents can take the form of guidelines to industry, letters, inspection guides, etc.

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industry with insight into the areas of training and special interest FDA investigators and scientists may have for a par- ticular subject. All of these documents, guidelines, and inspec- tional references are available in the public domain via the internet ( http: ==www.fda.gov ).

2.4. Pre-Approval Inspections In the United States, most drug and certain diagnostic device

products require pre-approval inspections (PAIs) before the FDA will grant product approval. Exceptions to this include minor supplements to existing new drug applications (NDAs) or abbreviated new drug applications (ANDAs) where the manufacturer has had recent inspections and =or a good regu- latory history. Major delays in product approval can be encountered when these PAIs do not meet FDA expectations. Additionally, weaknesses found during a PAI can direct FDA investigators into other areas within the firm’s quality sys- tems or development activities not originally within the scope of the PAI. For example, a poorly designed new product stabi- lity protocol can lead FDA investigators into the firm’s entire marketed product stability program. In another example, problems discovered on review of high performance liquid chromatograms can lead into an investigation of a firm’s entire analytical chemistry quality (QC) procedures. Adverse findings from a new product pre-approval have led to recalls and other serious regulatory actions for products already in the marketplace.

The PAI process was reinforced in 1988 after several firms were found to be providing false and misleading infor- mation to the FDA. This was known in the industry as the ‘‘Generic Drug Scandal,’’ where applications were filed frau- dulently, although manufacturing capability did not exist for the drug products submitted for market approval, and sta- bility data were falsified. Even though the problems were generated by a small number of companies, the entire phar- maceutical industry and the FDA were shaken by the incidents. Many individuals involved were found guilty of criminal activity and punished. Some individuals were

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banned from the US drug industry. The FDA maintains a black list of individuals who have been banned from develop- ing or manufacturing drugs for US consumption.

As a result of these tumultuous findings new require- ments for PAIs were developed. In the United States, product applications sent to Agency centers may be in perfect order but if significant issues arise at the factory or in the develop- ment laboratories during the PAI, the entire approval process can be delayed months or even years. It is, therefore, essential that all branches of manufacturing, including research and development departments prepare carefully for the PAI to assure a timely and successful outcome.

Even the best drug and device firms have demonstrated weaknesses in PAIs. The FDA records objectionable findings on a form known as the FDA-483 Notice of Inspectional Find- ings. Typical manufacturing and quality system weaknesses encountered during PAIs of the 1990s include:

Validation: Weak, faulty, or non-existent validations supporting the following: Processes such as mixing, sterilization, potency adjust- ments. Equipment such as fillers, sealers, processing and packaging equipment. Utilities: Medical grade product contact gases such as nitrogen, carbon dioxide, and oil free compressed air. Software: Processes controlled by computer; software used in QC calculations. Facilities: Floors, wall, and ceilings properly designed and constructed.

Aseptic processing: Media runs. Training of personnel in aseptic techniques. Environmental monitoring program weaknesses.

Specifications: Not adequate or present.

Sterility assurance: Problems with sterility testing.

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Sterilization process validation weaknesses. Closure system integrity.

Training (lack of adequate personnel training or docu- mentation thereof). GMP violation of bulk drug manufacturing processes including: Poor or lacking validation. Cleaning processes not validated. Impurity profile not understood. Deviations from established procedures. Sterility assurance and testing. Stability (pre-market, post-market, and packaging changes).

The FDA is very serious about enforcement and protec- tion of the public health. FDA investigators who perform PAIs are well armed with Agency-developed guidance documents and training. Some investigators have even received criminal investigator training. In most cases, however, the FDA inves- tigator tries to determine

that the data filed in the application were gathered under good laboratory and good manufacturing practices; if the manufacturing specifications developed thus far are appropriate to control the manufacturing process; if the firm is in substantial compliance to current good manufacturing practices; if the firm actually can adequately produce the material they have filed for.

2.5. Regulatory Enforcement The FDA can muster many levels of enforcement activity on the

firm under review. In order of severity they can do the following: Issue an FDA-483 report, generally considered to be

items the FDA investigator feels require attention by the firm. Sometimes these 483s are early warning signs to warrant additional regulatory action.

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Recommend withholding the application approval. This is very painful news to any firm trying to get a new product approved. Usually these recommenda- tions follow a PAI, or result from concerns at FDA Centers reviewing the application, or may be a result of continued unrelated GMP problems at a firm. Issue a Warning Letter. This is bad news. A Warning Letter tells the firm’s senior management they must develop and provide a responsive plan to the FDA’s concerns or further regulatory action may ensue. Boi- lerplate verbiage in warning letters may say ‘‘These deviations cause drug products manufactured by your firm to be adulterated within the meaning of Section

50 l(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)’’ and ‘‘You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action with- out further notice. These actions include, but are not limited to, seizure and injunction.’’ These actions can

be serious indeed. Warning Letters have cited problems on master batch

records, including poor identification of significant steps and failure to comply with the firm’s own requirements. Deficien- cies in identity testing, labeling violations, complaint hand- ling, stability testing inadequacies, and poor documentation have also been associated with Warning Letters.

FDA-483 observations can also cast doubt on a firm’s overall quality programs and the ability to get new products approved quickly. Examples of 483 observations involving injectable products include:

failure to investigate failures thoroughly, such as exceeding action levels on ingredient water samples, sterility test failures, and stability failures; not challenging product stability at upper limits of USP (United States Pharmacopeia) room temperature; lack of cleaning validation; lack of appropriate change control programs and poor execution of change control;

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reworking, re-inspecting or reprocessing drug sub- stances or products without adequate validation or supporting information; testing and reworking materials, ad infinitum, in order to meet a certain specification. failure to establish and implement sufficient controls to ensure processes are properly validated prior to drug products being released for sale. failure to perform periodic quality evaluations (audits).