Gary Messplay and Colleen Heisey11.06.08
The U.S. Food and Drug Administration ( FDA ) recently issued two final rules that update the regulations regarding current good manufacturing practices ( CGMP ) for human drug products. In a final rule published July 2008 and effective September 15, 2008, FDA amended CGMP regulations for human drugs and biological products to exempt most Phase I investigational new drugs from compliance with the CGMP requirements of Parts 210 and 211 of Title 21 of the U.S. Code of Federal Regulations. In addition, FDA acted in September to amend the CGMP regulations for finished pharmaceuticals to revise the requirements for aseptic processing , verification of performance of operations, the use of asbestos filters, and other minor changes, in order to modernize the "current" practices. The latter rule becomes effective December 8, 2008.
The general regulations guiding CGMP for human drugs are published in Parts 210 and 211 of Title 21 of the U.S. Code of Federal Regulations. In the preamble to Parts 210 and 211, FDA stated that the CGMP regulations apply to investigational products, but left open the possibility of an additional CGMP regulation to address drugs used in research. Specifically, the preamble explained, "[T]he Commissioner is considering proposing additional CGMP regulations specifically designed to cover drugs in research stages." FDA believes there are important differences among phases in clinical trials that warrant permitting different manufacturing standards for the product used in those trials. Generally, Phase I clinical trials involve the initial introduction of an investigational product into the human population, the results of which are used to evaluate and establish the basic safety of the investigational product. Typically, Phase I clinical trials are designed primarily to ascertain how the drug product acts in humans, including the metabolism of the drug by the human body as well as its pharmacologic activity. Relative to extensive Phase II and III clinical trials to evaluate safety and efficacy , Phase I trials are small, consisting of no more than 80 subjects on average. The ability to progress to Phase II and III clinical trials is based, in part, on the information derived from Phase I.
To address these differences, FDA previously considered relieving Phase I clinical trial drug products from the CGMP regulatory requirements of Part 210 and 211. In 2006, FDA published a direct to final rule proposing to exempt most Phase I investigational drugs from complying with these Parts. The Agency concurrently published an identical proposed rule in case it received "significant adverse comment," which is any comment that explains why the rule would be inappropriate, including challenges to the underlying premise for the rule, or would be unacceptable or ineffective without change. Because the Agency received significant adverse comments, FDA withdrew the direct to final rule. However, it moved forward in its consideration of the identical proposed rule.
In finalizing the rule, the Agency considered and addressed the 14 comments it received, several of which it considered significant adverse comments. Ultimately, FDA determined that Phase I trial material should be exempt from the CGMP requirements of Part 210 and 211, and has amended 210.2 to add a paragraph to the scope section of the regulations that explicitly provides that the production of investigational drugs used in Phase II trials pursuant to an investigational new drug application ( IND ) do not need to comply with Part 211 regulations.
FDA provides two rationales for why Phase I clinical trial drug product should be exempt from Parts 210 and 211. The Agency first posits that, even with an exemption, the investigational drug product remains subject to the statutory requirement that causes a drug to be adulterated if "the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practices," which assures the drug meets the requirements of the Federal Food, Drug, and Cosmetic Act. Second, FDA feels it exerts sufficient control over the drugs for use in Phase I trials through its existing oversight of the IND process, which requires, among other things, a formal submission of information on chemistry, manufacturing, and control ( CMC ) of the product, including descriptions of the composition, manufacture, and control of the investigational product. FDA has the authority to place a clinical hold on an IND should the Agency determine the study exposes subjects to unreasonable and significant risk.
While FDA is exempting most Phase I investigational new drugs from Parts 210 and 211, FDA makes clear that if a sponsor has available drug product for use in Phase II or III studies, an action that demonstrates the sponsor's intention to expose more subjects to the test product and that requires adherence to the CGMP requirements of Parts 210 and 211, any subsequent Phase I study by the sponsor must use product manufactured in compliance with Part 211.
FDA intends the final rule to help the drug development process by making the application of CGMP more efficient and appropriate for manufacture of product intended for use in the earliest stages of investigational use, i.e. Phase I clinical trial. To complement the final rule, FDA also announced the availability of "Guidance for Industry: CGMP for Phase 1 Investigational Drugs," which sets forth the Agency's recommended approaches for compliance with CGMP for investigational drugs used in Phase I trials.
FDA has also revised the drug CGMP regulations to clarify that written procedures intended to prevent microbial contamination of sterile drug products must contain the validation procedures of all aseptic processes as well as those for sterilization processes. In these revisions to CGMP amending 211.67(a), the Agency recognizes that for sterile drug product, sterilization is appropriate and, at times, even in addition to sanitization. The revised rules require that equipment and utensils be cleaned, maintained, and as appropriate to the nature of the drug, sanitized "and/or sterilized" at appropriate intervals. Revised 211.84(d)(6) incorporates a longstanding Agency view into regulation, mainly that microbiological tests are required before use of each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use. Revised 211.94(c) and 211.110(a), requires validation of depyrogenation processes for containers and closures and adds bioburden testing to in-process control procedures for sampling and testing, respectively.
FDA has updated its regulations at 210.3(b)(6) and 211.72 to remove the rules that previously allowed the limited use of asbestos-containing filters when processing injectable drug products. In fact, while the Agency had initially proposed to merely remove the references to asbestos filters from these regulations, FDA changed the language of the final rule to expressly prohibit the use of such filters.
Finally, FDA adopted language to acknowledge that some operations in the manufacturing process can be completed by automated equipment and verified by a human, rather than one person performing the process and a second individual verifying the correct performance of such process. Specifically, FDA added language specifying that automated equipment can be used to perform the following operations and satisfy the verification by a second person requirements of 211.68: charge-in of components and containers (211.101(c)); calculation of yields (211.103); equipment cleaning and maintenance (211.182); and batch production and control records (211.188(b)(11)).
FDA's intention with respect to the latter three final rules is not only to modernize certain regulatory requirements but also to harmonize them with other regulations and international standards. Notably, FDA tabled one proposed revision on plumbing. Current 211.48(a) requires the use of potable water supplied under continuous pressure in a plumbing system free of defects that could add to the contamination of any drug and that such water meet the standards for primary drinking water, established in regulation by the U.S. Environmental Protection Agency. FDA had proposed to remove the primary drinking water standard from the rule and instead require the water to be "safe for human consumption," a change that would have enhanced harmonization with foreign regulations, including those of Japan and the European Union (EU), and with standards set by the U.S. Pharmacopeia. In the preamble to the proposed rule, FDA opined that the proposed standard could be met by compliance with the EPA regulations or current EU or Japanese regulations for potable water used for pharmaceutical preparations. However, FDA received several comments objecting to the change, explaining that the proposed standard was "not sufficiently prescriptive" to protect human health. FDA noted that it will reconsider the standards for water in the next phase of the CGMP initiative.
The changes in the CGMP regulations, as well as comments made by FDA in the respective preambles, reflect the Agency's ongoing commitment to employ a risk-based approach to the regulation of drug manufacturing. FDA assures the community it will reassess and revise the CGMP regulations regularly to accommodate technological and scientific advances.
Investigational New Drugs Intended for Use in Clinical Trials
The general regulations guiding CGMP for human drugs are published in Parts 210 and 211 of Title 21 of the U.S. Code of Federal Regulations. In the preamble to Parts 210 and 211, FDA stated that the CGMP regulations apply to investigational products, but left open the possibility of an additional CGMP regulation to address drugs used in research. Specifically, the preamble explained, "[T]he Commissioner is considering proposing additional CGMP regulations specifically designed to cover drugs in research stages." FDA believes there are important differences among phases in clinical trials that warrant permitting different manufacturing standards for the product used in those trials. Generally, Phase I clinical trials involve the initial introduction of an investigational product into the human population, the results of which are used to evaluate and establish the basic safety of the investigational product. Typically, Phase I clinical trials are designed primarily to ascertain how the drug product acts in humans, including the metabolism of the drug by the human body as well as its pharmacologic activity. Relative to extensive Phase II and III clinical trials to evaluate safety and efficacy , Phase I trials are small, consisting of no more than 80 subjects on average. The ability to progress to Phase II and III clinical trials is based, in part, on the information derived from Phase I.
To address these differences, FDA previously considered relieving Phase I clinical trial drug products from the CGMP regulatory requirements of Part 210 and 211. In 2006, FDA published a direct to final rule proposing to exempt most Phase I investigational drugs from complying with these Parts. The Agency concurrently published an identical proposed rule in case it received "significant adverse comment," which is any comment that explains why the rule would be inappropriate, including challenges to the underlying premise for the rule, or would be unacceptable or ineffective without change. Because the Agency received significant adverse comments, FDA withdrew the direct to final rule. However, it moved forward in its consideration of the identical proposed rule.
In finalizing the rule, the Agency considered and addressed the 14 comments it received, several of which it considered significant adverse comments. Ultimately, FDA determined that Phase I trial material should be exempt from the CGMP requirements of Part 210 and 211, and has amended 210.2 to add a paragraph to the scope section of the regulations that explicitly provides that the production of investigational drugs used in Phase II trials pursuant to an investigational new drug application ( IND ) do not need to comply with Part 211 regulations.
FDA provides two rationales for why Phase I clinical trial drug product should be exempt from Parts 210 and 211. The Agency first posits that, even with an exemption, the investigational drug product remains subject to the statutory requirement that causes a drug to be adulterated if "the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practices," which assures the drug meets the requirements of the Federal Food, Drug, and Cosmetic Act. Second, FDA feels it exerts sufficient control over the drugs for use in Phase I trials through its existing oversight of the IND process, which requires, among other things, a formal submission of information on chemistry, manufacturing, and control ( CMC ) of the product, including descriptions of the composition, manufacture, and control of the investigational product. FDA has the authority to place a clinical hold on an IND should the Agency determine the study exposes subjects to unreasonable and significant risk.
While FDA is exempting most Phase I investigational new drugs from Parts 210 and 211, FDA makes clear that if a sponsor has available drug product for use in Phase II or III studies, an action that demonstrates the sponsor's intention to expose more subjects to the test product and that requires adherence to the CGMP requirements of Parts 210 and 211, any subsequent Phase I study by the sponsor must use product manufactured in compliance with Part 211.
FDA intends the final rule to help the drug development process by making the application of CGMP more efficient and appropriate for manufacture of product intended for use in the earliest stages of investigational use, i.e. Phase I clinical trial. To complement the final rule, FDA also announced the availability of "Guidance for Industry: CGMP for Phase 1 Investigational Drugs," which sets forth the Agency's recommended approaches for compliance with CGMP for investigational drugs used in Phase I trials.
Aseptic Processing
FDA has also revised the drug CGMP regulations to clarify that written procedures intended to prevent microbial contamination of sterile drug products must contain the validation procedures of all aseptic processes as well as those for sterilization processes. In these revisions to CGMP amending 211.67(a), the Agency recognizes that for sterile drug product, sterilization is appropriate and, at times, even in addition to sanitization. The revised rules require that equipment and utensils be cleaned, maintained, and as appropriate to the nature of the drug, sanitized "and/or sterilized" at appropriate intervals. Revised 211.84(d)(6) incorporates a longstanding Agency view into regulation, mainly that microbiological tests are required before use of each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use. Revised 211.94(c) and 211.110(a), requires validation of depyrogenation processes for containers and closures and adds bioburden testing to in-process control procedures for sampling and testing, respectively.
Asbestos Fillers
FDA has updated its regulations at 210.3(b)(6) and 211.72 to remove the rules that previously allowed the limited use of asbestos-containing filters when processing injectable drug products. In fact, while the Agency had initially proposed to merely remove the references to asbestos filters from these regulations, FDA changed the language of the final rule to expressly prohibit the use of such filters.
Verification by a Second Individual
Finally, FDA adopted language to acknowledge that some operations in the manufacturing process can be completed by automated equipment and verified by a human, rather than one person performing the process and a second individual verifying the correct performance of such process. Specifically, FDA added language specifying that automated equipment can be used to perform the following operations and satisfy the verification by a second person requirements of 211.68: charge-in of components and containers (211.101(c)); calculation of yields (211.103); equipment cleaning and maintenance (211.182); and batch production and control records (211.188(b)(11)).
FDA's intention with respect to the latter three final rules is not only to modernize certain regulatory requirements but also to harmonize them with other regulations and international standards. Notably, FDA tabled one proposed revision on plumbing. Current 211.48(a) requires the use of potable water supplied under continuous pressure in a plumbing system free of defects that could add to the contamination of any drug and that such water meet the standards for primary drinking water, established in regulation by the U.S. Environmental Protection Agency. FDA had proposed to remove the primary drinking water standard from the rule and instead require the water to be "safe for human consumption," a change that would have enhanced harmonization with foreign regulations, including those of Japan and the European Union (EU), and with standards set by the U.S. Pharmacopeia. In the preamble to the proposed rule, FDA opined that the proposed standard could be met by compliance with the EPA regulations or current EU or Japanese regulations for potable water used for pharmaceutical preparations. However, FDA received several comments objecting to the change, explaining that the proposed standard was "not sufficiently prescriptive" to protect human health. FDA noted that it will reconsider the standards for water in the next phase of the CGMP initiative.
The changes in the CGMP regulations, as well as comments made by FDA in the respective preambles, reflect the Agency's ongoing commitment to employ a risk-based approach to the regulation of drug manufacturing. FDA assures the community it will reassess and revise the CGMP regulations regularly to accommodate technological and scientific advances.
