Companies in the pharmaceutical industry focused on meeting regulatory and international standard requirements must be aware of the regulations established by US Food and Drug Administration and their corresponding items within 21 CFR Title 21 of the Code of Federal Regulations, which covers the manufacturing of drugs and other products regulated by the USFDA.
For the manufacturing of finished pharmaceuticals 21 CFR Part 210 describes how to achieve cGMP. Therefore, it is essential for anyone looking to manufacture pharmaceutical products within the United States either through local or foreign sourcing.
In this article we will understand 21 CFR parts 210 and 211, overview of key components of 21 CFR Part 210 and additional guidance concerning these parts. How compliance with 21 CFR helps to ensure that a pharmaceutical company is producing a quality product that is safe and will be accepted by regulators.
On the other hand, part 211 provides additional detail about the finished product and specifies the requirements for operating personnel, material, manufacturing process, packaging, labeling, storage, laboratory controls and record keeping in the pharmaceutical industry.
There are major consequences of non compliance with these requirements and can be significant and include regulatory actions such as warning letters, seizures, import prohibition and closure of facilities.
2. All personnel involved in either manufacturing or quality control activities must be qualified experience for their job descriptions.
3. Regular training on hygiene, processes, safety and cGMP regulations must be conducted and each manufacturer must maintain a training record and periodic evaluation for the effectiveness of training.
4. The number of employees in the company must be sufficient to complete all production tasks without creating a risk of contamination or production errors.
Recommendations: Maintain an organizational chart, document company’s rule and responsibilities, conduct regular training programs and maintain quality control unit independence from the manufacturing unit.
2. The facility should have an appropriate draining system, adequate lighting, adequate air circulation and adequate sanitization facilities.
3. All equipment should be designed, sized and located in a manner to allow for easy access to cleaning and maintenance.
4. All materials used for constructing and equipment should not create a reaction with any pharmaceutical product or contaminate any of the materials in any way.
5. Facilities, equipment and materials used to manufacture sterile or other high risk products must provide a facility and equipment configuration that supports the requirements of aseptic processing and that meets the cGMP pharmaceutical manufacturing requirements.
6. The procedure for cleaning, maintenance and calibration of pharmaceutical equipment must have been validated and documented. Any lubricants, grease or other substance that comes into contact with a pharmaceutical product must meet pharmaceutical grade specifications only.
Recommendations: The use of clean room designs and validated equipment, planned and preventive maintenance, cleaning and calibration schedules should be developed, implemented and maintained properly in whole facility and manufacturing process.
2. The storing, controlling, quarantining, sampling, testing and releasing of these materials must be done through written procedures and the qualification and documentation for suppliers is also required.
Recommendations: Maintain the list of approved vendors, perform quality checks on incoming materials, store all materials in a controlled environment and separate any quarantined or previously approved lots.
2. In-process controls and environmental monitoring should be defined for the manufacturing process and must be implemented during the manufacturing process. In process control parameters like mixing time, temperature, weights, cleaning procedure and preventive measures against cross contamination must be documented.
3. For sterile or aseptic manufacturing, a procedure for environmental monitoring of the product for microbial contamination, monitoring of air flow in clean rooms, monitoring the filtered air used in manufacturing areas and maintaining the sterilization record for all sterile equipment must be established.
Recommendations: Always use an approved BMR that defines critical process parameters, performing process checks and document all activities performed during the process for all critical operations.
2. All packing levels must be properly reconciled (check the number if labels before and after using in batch) and the packaging must be tempering proof and have verified accuracy of the packaging levels.
3. Expiration date, storage condition, product batch number and all other labeling data related to a product must be consistent with both validated stability data and product specifications.
Recommendations: Use packing and labeling control standard operating procedure and ensure packing label reconciliation and batch verification for accurate traceability of sensitive labeling and packaging.
2. The finished product and raw material must be tested in quality control to ensure that they meet the specified identity, purity and quality standards before release.
3. Stability studies, reserve sample storage and periodically testing as needed are mandatory parts of the long term quality assurance plan.
Recommendations: Utilize established and validated analytical methods, maintain validation and calibration documents, develop stability procedures for testing and develop a secure storage for the retained samples according to the standard operating procedures.
2. Each batch must have complete traceability from when the raw materials are received until the final product is released. It allows easy recalls and helps in investigations and audits.
3. Everything related to non-compliance events, deviations, product complaints, recalls and other failures must be documented and investigated with CAPA implementation.
Recommendations: Maintain a strong record control system so that every record is signed, securely stored and has controls established for deviation and CAPA logging.
2. To ensure compliance with cGMP regulations, periodic internal audits and management reviews should be performed to verify compliance and identify areas that need improvement.
3. Critical changes related to process, equipment or material should be processed through change control and risk management procedures.
Recommendations: Schedule regular internal audits, document all findings, implement CAPA to address findings and establish change control and risk assessment for quality control unit.
The primary region companies in USA must follow cGMP is to sell their drug products in USA. Therefore, if you are exporting drugs to the USA, it is essential to follow the cGMP or you will not be allowed entry. Also, if you are sending to another country and you follow cGMP, it gives you a good chance of successfully having your drug product accepted by that country’s health care system.
A well defined and regulated cGMP system provides the company with an opportunity to establish consistent procedures across multiple facilities that reduce variation in product output and minimize risks
It reduces the number of recalls and deviations, reworks and improves efficiency throughout the manufacturing operation.
Following good manufacturing practices encourages a culture of quality that includes written documentation, personal accountability, product traceability and continuous improvement. The cultural change that develops from these regulatory requirements can often be worth more than simply checking the regulatory requirements.
1) Gap Assessment: Compare your current facilities, systems, SOPs and documents against the requirements of 21 CFR part 210 and 211.
2) Quality Unit & Organization: Improve your organization’s quality control unit. Clearly separate it from production and define the roles and responsibilities of the staff in quality control unit.
3) Facility & Equipment Review: Evaluate the layout of your facility, its cleanliness, suitability for your equipment, the frequency and type of maintenance and instrument calibration schedule and any upgrade if necessary.
4) Documentation & SOPs: Write standard operating procedures (SOPs) for production, QC, cleaning, maintenance, control of changes, managing deviations from SOPs, packaging, labeling and storing of material and manage these SOPs in a controlled environment.
5) Personnel & Training: Ensure that all employees receive sufficient training regarding GMP, hygiene, documents and their responsibilities. Maintain training records and access competencies on a scheduled basis.
6) Batch Records & Process Controls: Include batch manufacturing records, in-process checks, environmental monitoring, validation of process steps critical to manufacturing of the product and an easily understood release process for product batch.
7) QC & Testing: Conduct method validation for all analytical tests, maintain compliance with QC laboratory requirements, conduct stability testing and manage retention of reserve samples.
8) Change Control & Risk Management: Conduct an impact assessment of all critical changes. Make appropriate approvals for change, run a revalidation of processes and equipment and maintain records of the outcome of these validation efforts.
9) Internal Audits & Quality Reviews: Schedule to conduct regular internal audits, maintain a corrective action tracking system, conduct management reviews and continuously improve the process based upon the results of the audits.
10) Continuous Monitoring & CAPA: Evaluate incidents of deviation, customer complaints, out of specification (OOS) results, leading to performing a detailed investigation (root cause analysis) and implementing corrective and preventive actions (CAPA) to ensure effectiveness.
11) Maintain Documentation and Records: Maintain appropriate documentation for all activities associated with manufacturing, testing, warehousing, shipping, customer complaints and recalls with traceability.
21 CFR is not solely limited to the United States but it also has a global impact. Using the 21 CFR as a basis of your product’s quality will help your business meet the quality expectation of most regulatory authority and customers around the world.
By providing an auditable quality process, 21 CFR compliance helps the business who are exporting to US and who are also selling to multiple international clients. With a simple process audit and verify compliance with 21CFR, business can improve their quality assurance and reduce the risk of product quality issues arising from regulatory noncompliance.
In addition, 21 CFR encourages businesses to implement good practices in documentation, validation, audit trails and data integrity, which will improve the quality and reliability of their products.
21 CFR has 3 Chapters and 1402 Parts but every part is not useful for pharmaceutical industry. Some parts useful for pharmaceutical industry are listed here.
This chapter is specifically meant for the Food and Drug Administration (FDA). It has been derived from the Federal food, drug and cosmetic act. This chapter has many sections dealing with various guidelines. Some of the most prominent ones are as follows:
11: Deals with rules concerning digital signatures and electronic records maintenance. The next few sections deal with clinical trials. It has FDA 21 CFR part 11 requirements.
50: Rules to protect human subjects in clinical trials.
54: Full disclosure of financial records by such clinical investigators.
56: Guidelines for institutional review boards that supervise such clinical trials.
58: Good Laboratory Practices.
The series in the 100 range relates to food.
101: It deals with the listing of nutritional values of various food items with sub-sections concentrating on nutritional elements such as trans-fat. The rest of the 100 series deals with specific food products such as infant formula, food additives, dietary supplements, etc.
The 200 and 300 series deals with how drugs are advertised and guidelines to over the counter drugs and good workplace practices.
The 500 series is similar to the 200 and 300 series but deals specifically with drugs and medications meant for animals and practices related to the veterinary sciences.
The 600 series covers biological substances both natural such as blood and lymph and man-made such as vaccines.
The 700 series involves everything from labeling to research involving cosmetics.
The 800 series is meant for medical devices, their hazard warnings, approvals needed before launching such a product and other safety regulations for such devices.
The 900 series regulates the devices and the standards necessary for devices used for mammography.
The 1000 series enforces requirements of devices that emit radiations such as mobile phones, x-ray machines, etc.
The 1100 series deals with tobacco products and expands upon the products that previously were not well defined and covered under tobacco products such as e-cigarettes, pipe tobacco, etc.
The 1200 series deals with rules not included in the food, drug and cosmetic act. Some examples are pasteurization of milk, import and export of turtles as pets, etc.
Though the Title 21 of the CFR and its recommendations are quite extensive there are still some ambiguity and gray areas that need to be ironed out, but all in all, it has improved over previous versions and has been updated to clear issues and confusions faced in previously unclear sections. It is necessary and recommended for FDA regulatory compliance.
Access Full 21CFR here
In this article we will understand 21 CFR parts 210 and 211, overview of key components of 21 CFR Part 210 and additional guidance concerning these parts. How compliance with 21 CFR helps to ensure that a pharmaceutical company is producing a quality product that is safe and will be accepted by regulators.
What is the Purpose of CFR (Parts 210 & 211)?
This section of CFR governs Food and Drugs in USA and dictates how the FDA operates. The goal of Part 210 is to establish general provisions and definitions for current Good Manufacturing Practices which serve as a foundation for all manufacturing, processing, packaging and storage of drugs.On the other hand, part 211 provides additional detail about the finished product and specifies the requirements for operating personnel, material, manufacturing process, packaging, labeling, storage, laboratory controls and record keeping in the pharmaceutical industry.
Who Needs to Comply with Parts 210/211?
Pharmaceutical manufacturing companies who manufacture, pack or hold finished pharmaceutical products including prescription drugs or over the counter drugs are required to comply with 21 CFR parts 210 and 211.There are major consequences of non compliance with these requirements and can be significant and include regulatory actions such as warning letters, seizures, import prohibition and closure of facilities.
Key Requirements for 21 CFR Compliance
21 CFR Part 11 establishes the minimum requirement for pharmaceutical manufacturers to comply with good manufacturing practices. The following sections provide a brief overview of 21 CFR Part 211 and its recommendation that pharmaceutical companies must implement.A. Organization and Personnel
1. A formally established, independent, knowledgeable quality control unit is essential that is responsible for approval or rejection of drugs, raw materials, packaging materials and labels as well as finished products.2. All personnel involved in either manufacturing or quality control activities must be qualified experience for their job descriptions.
3. Regular training on hygiene, processes, safety and cGMP regulations must be conducted and each manufacturer must maintain a training record and periodic evaluation for the effectiveness of training.
4. The number of employees in the company must be sufficient to complete all production tasks without creating a risk of contamination or production errors.
Recommendations: Maintain an organizational chart, document company’s rule and responsibilities, conduct regular training programs and maintain quality control unit independence from the manufacturing unit.
B. Facilities, Equipment, and Building
1. The design and maintenance of a facility to prevent the possibility of contamination requires a proper material selection for walls, floors and ceilings.2. The facility should have an appropriate draining system, adequate lighting, adequate air circulation and adequate sanitization facilities.
3. All equipment should be designed, sized and located in a manner to allow for easy access to cleaning and maintenance.
4. All materials used for constructing and equipment should not create a reaction with any pharmaceutical product or contaminate any of the materials in any way.
5. Facilities, equipment and materials used to manufacture sterile or other high risk products must provide a facility and equipment configuration that supports the requirements of aseptic processing and that meets the cGMP pharmaceutical manufacturing requirements.
6. The procedure for cleaning, maintenance and calibration of pharmaceutical equipment must have been validated and documented. Any lubricants, grease or other substance that comes into contact with a pharmaceutical product must meet pharmaceutical grade specifications only.
Recommendations: The use of clean room designs and validated equipment, planned and preventive maintenance, cleaning and calibration schedules should be developed, implemented and maintained properly in whole facility and manufacturing process.
C. Control of Components, Containers, and Closures
1. The identification, storage and control of all the raw materials, components, containers and closures must be appropriately stored and documented to avoid contamination and mixups.2. The storing, controlling, quarantining, sampling, testing and releasing of these materials must be done through written procedures and the qualification and documentation for suppliers is also required.
Recommendations: Maintain the list of approved vendors, perform quality checks on incoming materials, store all materials in a controlled environment and separate any quarantined or previously approved lots.
D. Production and Process Controls
1. All manufacturing processes must be documented in batch manufacturing record (BMR) or other similar document that describes any steps taken in detail during the manufacturing process.2. In-process controls and environmental monitoring should be defined for the manufacturing process and must be implemented during the manufacturing process. In process control parameters like mixing time, temperature, weights, cleaning procedure and preventive measures against cross contamination must be documented.
3. For sterile or aseptic manufacturing, a procedure for environmental monitoring of the product for microbial contamination, monitoring of air flow in clean rooms, monitoring the filtered air used in manufacturing areas and maintaining the sterilization record for all sterile equipment must be established.
Recommendations: Always use an approved BMR that defines critical process parameters, performing process checks and document all activities performed during the process for all critical operations.
E. Packaging and Labeling Control
1. Packaging material and packaging labels must be stored securely. Ensure proper line clearance procedures are being followed in order to prevent the mixing of the batches.2. All packing levels must be properly reconciled (check the number if labels before and after using in batch) and the packaging must be tempering proof and have verified accuracy of the packaging levels.
3. Expiration date, storage condition, product batch number and all other labeling data related to a product must be consistent with both validated stability data and product specifications.
Recommendations: Use packing and labeling control standard operating procedure and ensure packing label reconciliation and batch verification for accurate traceability of sensitive labeling and packaging.
F. Laboratory Controls and Testing
1. Laboratory performing quality control tests should be designed and equipped to perform testing under scientifically sound, documented and validated testing procedures. Laboratory equipment must be maintained and calibrated properly with a written calibration schedule.2. The finished product and raw material must be tested in quality control to ensure that they meet the specified identity, purity and quality standards before release.
3. Stability studies, reserve sample storage and periodically testing as needed are mandatory parts of the long term quality assurance plan.
Recommendations: Utilize established and validated analytical methods, maintain validation and calibration documents, develop stability procedures for testing and develop a secure storage for the retained samples according to the standard operating procedures.
G. Record Keeping and Documentation
1. All records related to manufacturing, testing, packaging, labelling, distribution and controls must be complete, accurate and easily retrievable including batch records, lab results, deviations, change controls, training records and cleaning logs.2. Each batch must have complete traceability from when the raw materials are received until the final product is released. It allows easy recalls and helps in investigations and audits.
3. Everything related to non-compliance events, deviations, product complaints, recalls and other failures must be documented and investigated with CAPA implementation.
Recommendations: Maintain a strong record control system so that every record is signed, securely stored and has controls established for deviation and CAPA logging.
H. Quality Unit Oversight and Review
1. Every component including material, container, closure in-process material and drug product that is produced must be reviewed and approved by the quality control unit.2. To ensure compliance with cGMP regulations, periodic internal audits and management reviews should be performed to verify compliance and identify areas that need improvement.
3. Critical changes related to process, equipment or material should be processed through change control and risk management procedures.
Recommendations: Schedule regular internal audits, document all findings, implement CAPA to address findings and establish change control and risk assessment for quality control unit.
Importance of 21 CFR Compliance for Companies
21 CFR often referred to as cGMP, which describes how a drug manufacturing company should produce their products following minimum safety and quality standards set forth by FDA.The primary region companies in USA must follow cGMP is to sell their drug products in USA. Therefore, if you are exporting drugs to the USA, it is essential to follow the cGMP or you will not be allowed entry. Also, if you are sending to another country and you follow cGMP, it gives you a good chance of successfully having your drug product accepted by that country’s health care system.
A well defined and regulated cGMP system provides the company with an opportunity to establish consistent procedures across multiple facilities that reduce variation in product output and minimize risks
It reduces the number of recalls and deviations, reworks and improves efficiency throughout the manufacturing operation.
Following good manufacturing practices encourages a culture of quality that includes written documentation, personal accountability, product traceability and continuous improvement. The cultural change that develops from these regulatory requirements can often be worth more than simply checking the regulatory requirements.
Practical Steps to Implement 21 CFR Recommendations
If your company wants to comply with 21 CFR then following is the simple step by step roadmap.1) Gap Assessment: Compare your current facilities, systems, SOPs and documents against the requirements of 21 CFR part 210 and 211.
2) Quality Unit & Organization: Improve your organization’s quality control unit. Clearly separate it from production and define the roles and responsibilities of the staff in quality control unit.
3) Facility & Equipment Review: Evaluate the layout of your facility, its cleanliness, suitability for your equipment, the frequency and type of maintenance and instrument calibration schedule and any upgrade if necessary.
4) Documentation & SOPs: Write standard operating procedures (SOPs) for production, QC, cleaning, maintenance, control of changes, managing deviations from SOPs, packaging, labeling and storing of material and manage these SOPs in a controlled environment.
5) Personnel & Training: Ensure that all employees receive sufficient training regarding GMP, hygiene, documents and their responsibilities. Maintain training records and access competencies on a scheduled basis.
6) Batch Records & Process Controls: Include batch manufacturing records, in-process checks, environmental monitoring, validation of process steps critical to manufacturing of the product and an easily understood release process for product batch.
7) QC & Testing: Conduct method validation for all analytical tests, maintain compliance with QC laboratory requirements, conduct stability testing and manage retention of reserve samples.
8) Change Control & Risk Management: Conduct an impact assessment of all critical changes. Make appropriate approvals for change, run a revalidation of processes and equipment and maintain records of the outcome of these validation efforts.
9) Internal Audits & Quality Reviews: Schedule to conduct regular internal audits, maintain a corrective action tracking system, conduct management reviews and continuously improve the process based upon the results of the audits.
10) Continuous Monitoring & CAPA: Evaluate incidents of deviation, customer complaints, out of specification (OOS) results, leading to performing a detailed investigation (root cause analysis) and implementing corrective and preventive actions (CAPA) to ensure effectiveness.
11) Maintain Documentation and Records: Maintain appropriate documentation for all activities associated with manufacturing, testing, warehousing, shipping, customer complaints and recalls with traceability.
21 CFR for Global Manufacturers
21 CFR is the primary regulatory framework for Good Manufacturing Practices in United States. 21 CFR compliance is beneficial to all businesses regardless of where they are registered and how they do business.21 CFR is not solely limited to the United States but it also has a global impact. Using the 21 CFR as a basis of your product’s quality will help your business meet the quality expectation of most regulatory authority and customers around the world.
By providing an auditable quality process, 21 CFR compliance helps the business who are exporting to US and who are also selling to multiple international clients. With a simple process audit and verify compliance with 21CFR, business can improve their quality assurance and reduce the risk of product quality issues arising from regulatory noncompliance.
In addition, 21 CFR encourages businesses to implement good practices in documentation, validation, audit trails and data integrity, which will improve the quality and reliability of their products.
List of 21CFR Sections Useful for Pharmaceutical Industry
21 CFR has 3 Chapters and 1402 Parts but every part is not useful for pharmaceutical industry. Some parts useful for pharmaceutical industry are listed here.
Chapter 1
This chapter is specifically meant for the Food and Drug Administration (FDA). It has been derived from the Federal food, drug and cosmetic act. This chapter has many sections dealing with various guidelines. Some of the most prominent ones are as follows:
11: Deals with rules concerning digital signatures and electronic records maintenance. The next few sections deal with clinical trials. It has FDA 21 CFR part 11 requirements.
50: Rules to protect human subjects in clinical trials.
54: Full disclosure of financial records by such clinical investigators.
56: Guidelines for institutional review boards that supervise such clinical trials.
58: Good Laboratory Practices.
The series in the 100 range relates to food.
101: It deals with the listing of nutritional values of various food items with sub-sections concentrating on nutritional elements such as trans-fat. The rest of the 100 series deals with specific food products such as infant formula, food additives, dietary supplements, etc.
The 200 and 300 series deals with how drugs are advertised and guidelines to over the counter drugs and good workplace practices.
The 500 series is similar to the 200 and 300 series but deals specifically with drugs and medications meant for animals and practices related to the veterinary sciences.
The 600 series covers biological substances both natural such as blood and lymph and man-made such as vaccines.
The 700 series involves everything from labeling to research involving cosmetics.
The 800 series is meant for medical devices, their hazard warnings, approvals needed before launching such a product and other safety regulations for such devices.
The 900 series regulates the devices and the standards necessary for devices used for mammography.
The 1000 series enforces requirements of devices that emit radiations such as mobile phones, x-ray machines, etc.
The 1100 series deals with tobacco products and expands upon the products that previously were not well defined and covered under tobacco products such as e-cigarettes, pipe tobacco, etc.
The 1200 series deals with rules not included in the food, drug and cosmetic act. Some examples are pasteurization of milk, import and export of turtles as pets, etc.
Chapter 2
This part of the 21 CFR concerns with the marketing, sale and use of controlled substances and scheduled drugs. It lists the various drugs and substances that need to be controlled and would require special documentation for buying and selling.Chapter 3
It primarily deals with rules concerning the implementation of a drug-free environment in government workplaces. These include lists of substances that are not allowed and the proper tests and procedures that employees at such places have to undergo. It also puts down the rules as to how often such tests have to be done.Though the Title 21 of the CFR and its recommendations are quite extensive there are still some ambiguity and gray areas that need to be ironed out, but all in all, it has improved over previous versions and has been updated to clear issues and confusions faced in previously unclear sections. It is necessary and recommended for FDA regulatory compliance.
Access Full 21CFR here
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