James A. Dunning, Owner, QPC Services LLC11.07.17
Anyone working in the pharmaceutical and/or medical device industries knows that both sectors are very dynamic markets. Each is unique in its own way, but the two share a common goal of bringing safe, effective products to market as quickly and efficiently as possible.
I’ve spent much of this year comparing parts of the drug and device industries’ Current Good Manufacturing Practices (cGMP) requirements, hoping to enlighten readers on the similarities I believe exist within the mandates. Clearly, the product approval process for drugs and devices is different, but both require knowledge of the proper documentation as well as an understanding of the elements for regulatory submission. Understanding the similarities and differences between the cGMP mandates is important for companies straddling both industries with combination drug-device products.
To conclude this cGMP comparison series, I will focus on ways 21 CFR Part 820 Quality System Regulation, also known as the cGMP regulation for medical devices, aligns with the cGMP requirements of 21 CFR Part 211 Subpart E —Control of Components and Drug Product Containers and Closures. As was the case in previous articles, the term “pharmaceutical(s)” is used rather than “drug(s)” unless the term is part of an excerpt from the cGMP regulation. Scope and definition are the same as well.
The first notable difference is the Pharmaceutical cGMP requirements are more specific in identifying drug product components, containers, and closures. The equivalent Medical Device cGMP mandates are more general, specifying requirements in terms of device specifications and process controls.
The second item of note is the Medical Device cGMP requirements do not contain a directive for retesting approved components. Subpart L—covering Handling, Storage, Distribution, and Installation—instructs the manufacturer to ensure that mixups, damage, deterioration, contamination, or other adverse effects to a product do not occur during handling, (820.140 Handling). However, retesting is not a specific requirement. In my experience, medical device companies manufacturing products with components susceptible to deterioration over time will perform retesting. This is particularly the case with combination devices.
Also of significance is the fact that Pharmaceutical cGMP requirement 211.94 (drug product containers and closures) is addressed in the Medical Device cGMP mandate 820.30 (design controls). Pharmaceutical design and development is a comprehensive process separate from the cGMP requirements. The comparison between the Pharmaceutical cGMP directive specified in 211.94 and the corresponding Medical Device cGMP requisites warrant a deeper dive. To make this analysis easier to follow, I cite the design controls process as 820.30(f) Design verification rather than mention all 820.30 requirements that would apply.
Pharmaceutical cGMP 211.94(a)
Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.
Medical Device cGMP 820.30(f) Design verification
Comments: The Pharmaceutical cGMP requirement is more specific in this section, stating the containers and closure should not be reactive, additive, or absorptive. The Medical Device cGMP in this section is more general, saying the design verification must confirm that design output meets design input requirements. If design activities determine components are not reactive, additive, or absorptive, then these requirements would be design inputs that are converted into specific design outputs and verified in accordance with 820.30(f) Design verification.
Pharmaceutical cGMP 211.94(b)
Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
Medical Device cGMP 820.30(f) Design verification, 820.130 Device packaging, and 820.150 Storage, paragraph (a)
Comments: The storage requirements defined in 211.94(b) are addressed in the Medical Device design control requirements. Storage condition requisites are also specified in 820.130 Device packaging, which reads, “Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.” Storage requirements are also specified in 820.150 Storage, which reads, “(a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its condition shall be assessed as appropriate.”
Pharmaceutical cGMP 211.94(c)
Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated.
Medical Device cGMP 820.30(f) Design verification, 820.75 Process validation
Comments: Medical device manufacturers are mandated to use the design process to establish that components must be pyrogen-free. Process validation, which would include sterilization and cleaning processes, is also required by the Medical Device cGMP requirements.
Pharmaceutical cGMP 211.94(d)
Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.
Medical Device cGMP 820.30(f) Design verification. 820.3(o) Definition of Manufacturer, and 820.75(a) Process Validation
Comments: This requirement is addressed through the design process. Additionally, 820.3 Definitions, paragraph (o), states “Manufacturer means any person who designs, manufactures, fabricates, assembles, or processes a finished device. Manufacturer includes but is not limited to those who perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions.” Finally, 820.75(a) Process validation reads “(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.”
Pharmaceutical cGMP 211.94(e)
Medical gas containers and closures must meet the following requirements—(1) Gas-specific use outlet connections. Portable cryogenic medical gas containers that are not manufactured with permanent gas use outlet connections (e.g., those that have been silver-brazed) must have gas-specific use outlet connections that are attached to the valve body so that they cannot be readily removed or replaced (without making the valve inoperable and preventing the containers’ use) except by the manufacturer. For the purposes of this paragraph, the term “manufacturer” includes any individual or firm that fills high-pressure medical gas cylinders or cryogenic medical gas containers. For the purposes of this section, a “portable cryogenic medical gas container” is one that is capable of being transported and is intended to be attached to a medical gas supply system within a hospital, healthcare entity, nursing home, other facility, or home healthcare setting, or is a base unit used to fill small cryogenic gas containers for use by individual patients. The term does not include cryogenic containers that are not designed to be connected to a medical gas supply system, e.g., tank trucks, trailers, rail cars, or small cryogenic gas containers for use by individual patients (including portable liquid oxygen units as defined at §868.5655 of this chapter). (2) Label and coloring requirements. The labeling specified at §201.328(a) of this chapter must be affixed to the container in a manner that does not interfere with other labeling and such that it is not susceptible to becoming worn or inadvertently detached during normal use. Each such label as well as materials used for coloring medical gas containers must be reasonably resistant to fading, durable when exposed to atmospheric conditions, and not readily soluble in water.
Medical Device cGMP 820.30(f) Design verification. 820.120 Device labeling
Comments: Indeed, the Medical Device cGMP requirements address labeling requirements, though the mandates for medical gas containers and connections, as well as color additives are not specified. However, the requirements for medical gasses and color additives, when applicable, would be addressed through the Medical Device design process. Labeling is tackled specifically in 820.120 Device Labeling, paragraph (a), which reads “Each manufacturer shall establish and maintain procedures to control labeling activities. (a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary conditions of processing.”
Finally, it is particularly notable that the Pharmaceutical cGMP requirements Subpart E, are specified in three sub-sections of the Medical Device cGMP requirements (Subparts C, G, H, K, L, and O).
In conclusion, I believe both industries’ cGMP requirements are equivalent regarding the control of components, since the design controls process for medical devices that require product containers and closures would lead to equivalent mandates.
Further Reading
Review any of the other sections of this series by clicking on its headline.
Current Good Manufacturing Practices: Pharma vs. Device
Comparing cGMP Pharma vs. Device: Subpart A – General Provisions
Comparing cGMP Pharma vs. Device: Subpart A—General Provisions (Part II)
Comparing cGMP Pharma vs. Device: Subpart B—Organization and Personnel
Comparing cGMP Pharma vs. Device: Subpart C—Buildings and Facilities and Subpart D—Equipment
James A. “Jim” Dunning’s consulting career began in 2001. He has provided quality and regulatory consulting services for various companies ranging from Fortune 500 medical device firms to startups. Dunning’s passion, however, lies with startups and small companies, especially those in regulatory distress. He has amassed significant experience in preparing 510(k) applications, developing complete Quality Management Systems, providing Quality System Training, and advising on quality, business, and leadership issues. Dunning is a senior member of the American Society for Quality (ASQ) and a member of the Regulatory Affairs Professional Society (RAPS). He can be reached at jdunning@qpcservices.com.
I’ve spent much of this year comparing parts of the drug and device industries’ Current Good Manufacturing Practices (cGMP) requirements, hoping to enlighten readers on the similarities I believe exist within the mandates. Clearly, the product approval process for drugs and devices is different, but both require knowledge of the proper documentation as well as an understanding of the elements for regulatory submission. Understanding the similarities and differences between the cGMP mandates is important for companies straddling both industries with combination drug-device products.
To conclude this cGMP comparison series, I will focus on ways 21 CFR Part 820 Quality System Regulation, also known as the cGMP regulation for medical devices, aligns with the cGMP requirements of 21 CFR Part 211 Subpart E —Control of Components and Drug Product Containers and Closures. As was the case in previous articles, the term “pharmaceutical(s)” is used rather than “drug(s)” unless the term is part of an excerpt from the cGMP regulation. Scope and definition are the same as well.
The first notable difference is the Pharmaceutical cGMP requirements are more specific in identifying drug product components, containers, and closures. The equivalent Medical Device cGMP mandates are more general, specifying requirements in terms of device specifications and process controls.
The second item of note is the Medical Device cGMP requirements do not contain a directive for retesting approved components. Subpart L—covering Handling, Storage, Distribution, and Installation—instructs the manufacturer to ensure that mixups, damage, deterioration, contamination, or other adverse effects to a product do not occur during handling, (820.140 Handling). However, retesting is not a specific requirement. In my experience, medical device companies manufacturing products with components susceptible to deterioration over time will perform retesting. This is particularly the case with combination devices.
Also of significance is the fact that Pharmaceutical cGMP requirement 211.94 (drug product containers and closures) is addressed in the Medical Device cGMP mandate 820.30 (design controls). Pharmaceutical design and development is a comprehensive process separate from the cGMP requirements. The comparison between the Pharmaceutical cGMP directive specified in 211.94 and the corresponding Medical Device cGMP requisites warrant a deeper dive. To make this analysis easier to follow, I cite the design controls process as 820.30(f) Design verification rather than mention all 820.30 requirements that would apply.
Pharmaceutical cGMP 211.94(a)
Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.
Medical Device cGMP 820.30(f) Design verification
Comments: The Pharmaceutical cGMP requirement is more specific in this section, stating the containers and closure should not be reactive, additive, or absorptive. The Medical Device cGMP in this section is more general, saying the design verification must confirm that design output meets design input requirements. If design activities determine components are not reactive, additive, or absorptive, then these requirements would be design inputs that are converted into specific design outputs and verified in accordance with 820.30(f) Design verification.
Pharmaceutical cGMP 211.94(b)
Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
Medical Device cGMP 820.30(f) Design verification, 820.130 Device packaging, and 820.150 Storage, paragraph (a)
Comments: The storage requirements defined in 211.94(b) are addressed in the Medical Device design control requirements. Storage condition requisites are also specified in 820.130 Device packaging, which reads, “Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.” Storage requirements are also specified in 820.150 Storage, which reads, “(a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its condition shall be assessed as appropriate.”
Pharmaceutical cGMP 211.94(c)
Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated.
Medical Device cGMP 820.30(f) Design verification, 820.75 Process validation
Comments: Medical device manufacturers are mandated to use the design process to establish that components must be pyrogen-free. Process validation, which would include sterilization and cleaning processes, is also required by the Medical Device cGMP requirements.
Pharmaceutical cGMP 211.94(d)
Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.
Medical Device cGMP 820.30(f) Design verification. 820.3(o) Definition of Manufacturer, and 820.75(a) Process Validation
Comments: This requirement is addressed through the design process. Additionally, 820.3 Definitions, paragraph (o), states “Manufacturer means any person who designs, manufactures, fabricates, assembles, or processes a finished device. Manufacturer includes but is not limited to those who perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions.” Finally, 820.75(a) Process validation reads “(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.”
Pharmaceutical cGMP 211.94(e)
Medical gas containers and closures must meet the following requirements—(1) Gas-specific use outlet connections. Portable cryogenic medical gas containers that are not manufactured with permanent gas use outlet connections (e.g., those that have been silver-brazed) must have gas-specific use outlet connections that are attached to the valve body so that they cannot be readily removed or replaced (without making the valve inoperable and preventing the containers’ use) except by the manufacturer. For the purposes of this paragraph, the term “manufacturer” includes any individual or firm that fills high-pressure medical gas cylinders or cryogenic medical gas containers. For the purposes of this section, a “portable cryogenic medical gas container” is one that is capable of being transported and is intended to be attached to a medical gas supply system within a hospital, healthcare entity, nursing home, other facility, or home healthcare setting, or is a base unit used to fill small cryogenic gas containers for use by individual patients. The term does not include cryogenic containers that are not designed to be connected to a medical gas supply system, e.g., tank trucks, trailers, rail cars, or small cryogenic gas containers for use by individual patients (including portable liquid oxygen units as defined at §868.5655 of this chapter). (2) Label and coloring requirements. The labeling specified at §201.328(a) of this chapter must be affixed to the container in a manner that does not interfere with other labeling and such that it is not susceptible to becoming worn or inadvertently detached during normal use. Each such label as well as materials used for coloring medical gas containers must be reasonably resistant to fading, durable when exposed to atmospheric conditions, and not readily soluble in water.
Medical Device cGMP 820.30(f) Design verification. 820.120 Device labeling
Comments: Indeed, the Medical Device cGMP requirements address labeling requirements, though the mandates for medical gas containers and connections, as well as color additives are not specified. However, the requirements for medical gasses and color additives, when applicable, would be addressed through the Medical Device design process. Labeling is tackled specifically in 820.120 Device Labeling, paragraph (a), which reads “Each manufacturer shall establish and maintain procedures to control labeling activities. (a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary conditions of processing.”
Finally, it is particularly notable that the Pharmaceutical cGMP requirements Subpart E, are specified in three sub-sections of the Medical Device cGMP requirements (Subparts C, G, H, K, L, and O).
In conclusion, I believe both industries’ cGMP requirements are equivalent regarding the control of components, since the design controls process for medical devices that require product containers and closures would lead to equivalent mandates.
Further Reading
Review any of the other sections of this series by clicking on its headline.
Current Good Manufacturing Practices: Pharma vs. Device
Comparing cGMP Pharma vs. Device: Subpart A – General Provisions
Comparing cGMP Pharma vs. Device: Subpart A—General Provisions (Part II)
Comparing cGMP Pharma vs. Device: Subpart B—Organization and Personnel
Comparing cGMP Pharma vs. Device: Subpart C—Buildings and Facilities and Subpart D—Equipment
James A. “Jim” Dunning’s consulting career began in 2001. He has provided quality and regulatory consulting services for various companies ranging from Fortune 500 medical device firms to startups. Dunning’s passion, however, lies with startups and small companies, especially those in regulatory distress. He has amassed significant experience in preparing 510(k) applications, developing complete Quality Management Systems, providing Quality System Training, and advising on quality, business, and leadership issues. Dunning is a senior member of the American Society for Quality (ASQ) and a member of the Regulatory Affairs Professional Society (RAPS). He can be reached at jdunning@qpcservices.com.
