5.3: Current Good Manufacturing Practices (CGMPs) - Biology

5.3: Current Good Manufacturing Practices (CGMPs) - Biology

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These guidelines for product manufacturing and testing represent a formal quality system that describes the general principles that must be observed during manufacturing. It is the company's responsibility to ensure GMP compliance and to do so efficiently and effectively. To this end, regulations are relatively flexible. It is up to the manufacturer to establish design procedures, processing methods, and testing procedures. This flexibility gives companies room to experiment and innovate.

Published in 1963, the first set of Good Manufacturing Practices (GMP) was intended to prevent deaths and injuries from contaminated products. These regulations seek to ensure the quality and purity of drugs products from batch-to-batch and put a system in place to detect and reduce errors and variation in manufacturing. In 1990, the FDA revised CGMP regulation to add the design controls authorized by the Safe Medical Devices Act. The FDA believed that it would be beneficial to the public and the medical device industry for the CGMP regulation to be consistent with international standards ISO 9001:1994 and ISO/CD 13485 "Quality Systems--Medical Devices--Supplementary Requirements to ISO 9001.” After an extensive effort, the part 820 revision was published on October 7, 1996 (61 FR 52602), and went into effect June 1, 1997.

Additionally, it should be noted that CGMPs represent only the currently accepted minimum standards for manufacturing, testing, and packaging drugs and medical devices. Most companies go beyond minimum guidelines to assure a customer a high-quality product. They frequently employ multiple quality systems, including voluntary ones, which gives the consumer peace of mind and a level of trust in the safety of the product.

GMP Guidelines Follow a Few Basic Principles:

  1. Define, control, and validate all critical manufacturing processes.
  2. Changes to the manufacturing process must be evaluated and approved.
  3. Instructions and procedures must be written and easy to understand.
  4. Production operators must receive thorough training
  5. The company must maintain accurate records demonstrating their adherence to guidelines and regulations.
  6. Records must be comprehensive, complete, and easily accessible.
  7. In the case of pharmaceuticals, quality is not diminished in any way by the distribution process.
  8. A recall system is in place so that any batch of a drug may be easily recalled from sale or supply.
  9. The company responds to complaints, quality defects are investigated, and appropriate measures are taken to prevent future errors.

CGMP Regulations

GMP regulations are included in Title 21 Chapter 1 of the CFR, in three regulations dealing with different types of manufactured products:

  1. for drugs (21 CFR 211)
  2. for medical devices (21 CFR 820)
  3. for blood and blood components (21 CFR 606)

The general principles of CGMP that all these regulations have in common:

  1. Quality, safety, and effectiveness are designed and built into the product, not tested or inspected into the product.
  2. Each step in the manufacturing process is documented and controlled to ensure that the finished product meets design and compendia specifications.
  3. Process documentation provides evidence of compliance with CGMPs.

Three primary criteria used by the FDA in the design of these CGMP regulations:

  1. Regulations should contain objectives and not detailed specifications. They should allow latitude for different manufacturers to find their means of compliance.
  2. Regulations should contain requirements that are considered feasible and valuable as recognized and considered by experts as assuring quality.
  3. If a practice can be established to be reasonable and relevant, then it can be a required practice even though it does not exist in the regulations.

Designing a GMP-Complaint Process

  1. The purpose of the process must be defined; that is, the desired output must be determined.
  2. An endpoint(s) that demonstrates the process is performed satisfactorily must be defined.
  3. A method to measure the desired endpoint is required.
  4. Raw materials and their specifications must be established.
  5. The steps in the process must be determined, usually by experimentation.
  6. The process must be scaled-up for production.
  7. An analysis of potential problems must be performed, noting the "critical points."
  8. Experiments must be carried out to determine how the process must operate at each critical point to make a quality product.
  9. Methods to monitor the process must be developed.
  10. Methods to control the process must be developed.
  11. Adequate record-keeping procedures must be developed.
  12. All SOPs required for the process must be written and approved.

Corrective Action Preventative Action (CAPA)

CAPA is an important part of any CGMP design and focuses on the systematic investigation of root causes of issues in the manufacturing process. CAPA is a way in which manufacturers can implement continuous improvement plans and Quality Management systems and have a large impact on FDA compliance. There are three main CAPA categories: Corrective actions that have never occurred, Corrective Actions of reoccurrences, and Preventative Action to prevent an occurrence. CAPA is mandatory for medical device manufacturing, and we will discuss CAPA more in the medical device chapter. Learn more about CAPA here:

Setting standards for quality in the biotechnology industry is difficult due to the often new and complex manufacturing processes involved. How should the FDA set quality standards, for example, for chromatographic purification systems? These processes are difficult to validate and represent ‘gray’ areas where quality regulations are concerned. For this reason, companies frequently rely on regulations that the FDA has not yet finalized, and they comply voluntarily with CGMPs and Guidelines.

The CGMPs for Medical Device, Pharmaceuticals & Biologics will be further explored in those respective chapters. The commonality between the three products in CGMP regulations is that the regulations are intended to ensure the safety and efficacy of those products. Failure to abide by CGMP requirements may result in adulterated products and FDA enforcement repercussions (explored in a later chapter). As regulations change, manufacturers must learn and comply with the new regulations. Continuous improvement, CAPA, internal audits, and FDA inspections all work together to ensure Quality by Design, and not by testing.

Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain-based vaccine candidate, RBD219-N1C1

A SARS-CoV-2 RBD219-N1C1 (RBD219-N1C1) recombinant protein antigen formulated on Alhydrogel® has recently been shown to elicit a robust neutralizing antibody response against SARS-CoV-2 pseudovirus in mice. The antigen has been produced under current good manufacturing practices (cGMPs) and is now in clinical testing. Here, we report on process development and scale-up optimization for upstream fermentation and downstream purification of the antigen. This includes production at the 1-L and 5-L scales in the yeast, Pichia pastoris, and the comparison of three different chromatographic purification methods. This culminated in the selection of a process to produce RBD219-N1C1 with a yield of >400 mg per liter of fermentation with >92% purity and >39% target product recovery after purification. In addition, we show the results from analytical studies, including SEC-HPLC, DLS, and an ACE2 receptor binding assay that were performed to characterize the purified proteins to select the best purification process. Finally, we propose an optimized upstream fermentation and downstream purification process that generates quality RBD219-N1C1 protein antigen and is fully scalable at a low cost. KEY POINTS: • Yeast fermentation conditions for a recombinant COVID-19 vaccine were determined. • Three purification protocols for a COVID-19 vaccine antigen were compared. • Reproducibility of a scalable, low-cost process for a COVID-19 vaccine was shown. Graphical abstract.

Keywords: COVID-19 Fermentation Pichia pastoris Purification Spike protein.

Conflict of interest statement

The authors declare no competing interests.


Fermentation ( a ) and…

Fermentation ( a ) and purification ( b ) flow diagrams. Three purification…

Timepoint SDS-PAGE analysis of pre-…

Timepoint SDS-PAGE analysis of pre- and post-induction fermentation samples of the lockdown process…

In-process sample comparison from three…

In-process sample comparison from three processes. Yield, step recovery, overall recovery, and purity…

Characterization of purified RBD219-N1C1 proteins…

Characterization of purified RBD219-N1C1 proteins from three processes. Purified proteins were analyzed by…

Impurity evaluation of the purified…

Impurity evaluation of the purified RBD219-N1C1 proteins from three processes. Unpurified (FS) and…

Binding ability of the purified…

Binding ability of the purified RBD219-N1C1 from three processes to a recombinant human…

What is GMP?

GMP refers to the Good Manufacturing Practice regulations promulgated by the US Food and Drug Administration under the authority of the Federal Food, Drug, and Cosmetic Act (See Chapter IV for food, and Chapter V, Subchapters A, B, C, D, and E for drugs and devices.) These regulations, which have the force of law, require that manufacturers, processors, and packagers of drugs, medical devices, some food, and blood take proactive steps to ensure that their products are safe, pure, and effective.

GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mixups, and errors. This protects the consumer from purchasing a product which is not effective or even dangerous. Failure of firms to comply with GMP regulations can result in very serious consequences including recall, seizure, fines, and jail time.

GMP regulations address issues including record keeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. Most GMP requirements are very general and open-ended, allowing each manufacturer to decide individually how to best implement the necessary controls. This provides much flexibility, but also requires that the manufacturer interpret the requirements in a manner which makes sense for each individual business.

GMP is also sometimes referred to as "cGMP". The "c" stands for "current," reminding manufacturers that they must employ technologies and systems which are up-to-date in order to comply with the regulation. Systems and equipment used to prevent contamination, mixups, and errors, which may have been first-rate 20 years ago may be less than adequate by current standards.

What is GMP?

The term GMP refers to Good Manufacturing Practice Regulations. These regulations have been implemented by the Food and Drug Administration Authority of United States. The regulations were implemented in accordance with the Federal Drug, Food and Cosmetic Act.

The GMP regulations are applicable for manufacturers, packagers and processors of medical devices, drugs and certain food items. The regulations will make sure that the products are completely safe for the people to use. In addition, the regulations ensure the effectiveness and purity of the products as well.

With GMP, all chances available for the manufacturers to end up with errors, mix-ups and contamination are eliminated. Hence, consumers will be able to ensure safety while they are purchasing the goods. The major sectors GMP covers include building and facilities, equipment, raw materials, personnel, production, labeling and complaints. GMP covers broad guidelines that should be adhered to by all companies in manufacturing. Here, there are no options or alternatives as the prior CGMP.

Some of the questions asked in this sector include:

  • Are the buildings and facilities being used in suitable size and design?
  • Are the personnel handling the processes well trained and equipped?
  • Are the raw materials stored and handled in ways which prevent mix-ups and cross-contamination?
  • Are there proper means of documenting production batches and records storage?

Requirements for clinical islet laboratories

General requirements for a clinical auto islet lab

The FDA expects that health-care institutions performing clinical auto islet transplants have the regulatory components described in 21CFR1271 (Tissue Rules) in place before transplanting its first patient. Unlike allogeneic islets, in which institutions must demonstrate safety, and in some cases, efficacy, there are no such requirements for auto islet programs when completing the FDA Tissue Establishment Registration. Nor are auto islet programs compelled to ongoing reporting to the FDA as is the case with allogeneic islets operating under an IND. Therefore, it is essential that clinical auto islet labs and the health-care institutions under which they operate police themselves rigorously. The Tissue Rules provides clinical islet labs not only the foundation but also concrete guidelines from which to work safely.

The following sections outline the specifics that the Tissue Rules require of labs manufacturing auto islet cells for human use. Adhering to these requirements are necessary to prevent the contamination of the clinical islet prep during the manufacturing process. Requirements include that each clinical auto islet lab has policies that address:

💊 GMP Guide

Good Manufacturing Practices (cGMP) for the food industry complements the HACCP (Hazard Analysis Critical Control Points) program. 21 CFR Part 110 deals with food sanitation, food handling and food preparation issues. 21 CFR 106 deals with a specific food subset - infant formula. 21 CFR 117 deals with risk management issues around food.

Closely related is 21 CFR Part 111 - Supplement GMP that effects the dietary supplement industry. Although dietary supplements are regulated by the FDA as foods, they are treated differently from foods and from drugs.

TITLE 21 - Food and Drugs


Subpart A - General Provisions

106.1 Status and applicability of the regulations in part 106.
106.3 Definitions.

Subpart B - Current Good Manufacturing Practice

106.5 Current good manufacturing practice.
106.6 Production and in-process control system.
106.10 Controls to prevent adulteration by workers.
106.20 Controls to prevent adulteration caused by facilities.
106.30 Controls to prevent adulteration caused by equipment or utensils.
106.35 Controls to prevent adulteration due to automatic (mechanical or electronic) equipment.
106.40 Controls to prevent adulteration caused by ingredients, containers, and closures.
106.50 Controls to prevent adulteration during manufacturing.
106.55 Controls to prevent adulteration from microorganisms.
106.60 Controls to prevent adulteration during packaging and labeling of infant formula.
106.70 Controls on the release of finished infant formula.
106.80 Traceability.
106.90 Audits of current good manufacturing practice.

Subpart C - Quality Control Procedures

106.91 General quality control.
106.92 Audits of quality control procedures.

Subpart D - Conduct of Audits

106.94 Audit plans and procedures.

Subpart E - Quality Factors for Infant Formulas

106.96 Requirements for quality factors for infant formulas.

Subpart F -Records and Reports

Subpart G - Registration, Submission, and Notification Requirements

106.110 New infant formula registration.
106.120 New infant formula submission.
106.121 Quality factor assurances for infant formulas.
106.130 Verification submission. 106.140 Submission concerning a change in infant formula that may adulterate the product.
106.150 Notification of an adulterated or misbranded infant formula.
106.160 Incorporation by reference.


Subpart A - General Provisions

110.3 Definitions.
110.5 Current good manufacturing practice.
110.10 Personnel.
110.19 Exclusions.

Subpart B - Buildings and Facilities

110.20 Plant and grounds.
110.35 Sanitary operations.
110.37 Sanitary facilities and controls.

Subpart C - Equipment

110.40 Equipment and utensils.

Subpart D - [Reserved]

Subpart E - Production and Process Controls

110.80 Processes and controls.
110.93 Warehousing and distribution.

Subpart F - [Reserved]

Subpart G - Defect Action Levels

110.110 Natural or unavoidable defects in food for human use that present no health hazard.


Subpart A - General Provisions

117.1 Applicability and status.
117.3 Definitions.
117.4 Qualifications of individuals who manufacture, process, pack, or hold food.
117.5 Exemptions.
117.7 Applicability of subparts C, D, and G of this part to a facility solely engaged in the storage of unexposed packaged food.
117.8 Applicability of subpart B of this part to the off-farm packing and holding of raw agricultural commodities.
117.9 Records required for this subpart.

Subpart B - Current Good Manufacturing Practice

117.10 Personnel.
117.20 Plant and grounds.
117.35 Sanitary operations.
117.37 Sanitary facilities and controls.
117.40 Equipment and utensils.
117.80 Processes and controls.
117.93 Warehousing and distribution.
117.95 Holding and distribution of human food by-products for use as animal food.
117.110 Defect action levels.

Subpart C - Hazard Analysis and Risk-Based Preventive Controls

117.126 Food safety plan.
117.130 Hazard analysis.
117.135 Preventive controls.
117.136 Circumstances in which the owner, operator, or agent in charge of a manufacturing/processing facility is not required to implement a preventive control.
117.137 Provision of assurances required under ?117.136(a)(2), (3), and (4).
117.139 Recall plan.
117.140 Preventive control management components.
117.145 Monitoring.
117.150 Corrective actions and corrections.
117.155 Verification.
117.160 Validation.
117.165 Verification of implementation and effectiveness.
117.170 Reanalysis.
117.180 Requirements applicable to a preventive controls qualified individual and a qualified auditor.
117.190 Implementation records required for this subpart.

Subpart D - Modified Requirements

117.201 Modified requirements that apply to a qualified facility.
117.206 Modified requirements that apply to a facility solely engaged in the storage of unexposed packaged food.

Subpart E - Withdrawal of a Qualified Facility Exemption

117.251 Circumstances that may lead FDA to withdraw a qualified facility exemption.
117.254 Issuance of an order to withdraw a qualified facility exemption.
117.257 Contents of an order to withdraw a qualified facility exemption.
117.260 Compliance with, or appeal of, an order to withdraw a qualified facility exemption.
117.264 Procedure for submitting an appeal.
117.267 Procedure for requesting an informal hearing.
117.270 Requirements applicable to an informal hearing.
117.274 Presiding officer for an appeal and for an informal hearing.
117.277 Timeframe for issuing a decision on an appeal.
117.280 Revocation of an order to withdraw a qualified facility exemption.
117.284 Final agency action.
117.287 Reinstatement of a qualified facility exemption that was withdrawn.

Subpart F - Requirements Applying to Records That Must Be Established and Maintained

117.301 Records subject to the requirements of this subpart.
117.305 General requirements applying to records.
117.310 Additional requirements applying to the food safety plan.
117.315 Requirements for record retention.
117.320 Requirements for official review.
117.325 Public disclosure.
117.330 Use of existing records.
117.335 Special requirements applicable to a written assurance.

Subpart G - Supply-Chain Program

117.405 Requirement to establish and implement a supply-chain program.
117.410 General requirements applicable to a supply-chain program.
117.415 Responsibilities of the receiving facility.
117.420 Using approved suppliers.
117.425 Determining appropriate supplier verification activities (including determining the frequency of conducting the activity).
117.430 Conducting supplier verification activities for raw materials and other ingredients.
117.435 Onsite audit.
117.475 Records documenting the supply-chain program.


File Name Document
Food Safety Training, Consulting and Certification English
SCS Food Safety Courses - Quick Guide English

Q - How do I get “certified” to HACCP?

A - Attending a HACCP training class does not grant “certification” to the attendee. A “Certificate” of Attendance (or Completion) is presented to attendees for completing the course. Having the ability to show an auditor or government inspector your issued Certificate of Attendance for the 16-hour HACCP course will satisfy training requirements for third-party audits, including GFSI programs like SQF, BRCGS, PrimusGFS, etc..

Q- How do Good Manufacturing Practices (cGMPs) relate to HACCP?

A - GMPs are food safety and quality goals published in Title 21 of the Code of Federal Regulations, Part 117 – Subpart B. The “c” in cGMP stands for current which indicates that the most recent standards. GMPs describe the methods, equipment, facilities, and controls for producing processed food. Five key elements, which are often referred to as the 5 P's of GMPs —people, premises, processes, products and procedures (or paperwork). And if all five are done well, there is a sixth P… profit! Some GMP Guidelines include Quality management, Sanitation and hygiene, Building and facilities/premises, Equipment, Raw materials, Personnel, and more. GMPs are part of the foundational programs, known as Pre-Requisite Programs, that support HACCP-based Food Safety Management Systems.

Q - What are Standard Operating Procedures (SOP)?

A - Directions, or practices, are directed by written SOPs. An SOP should be procedural and narrow in scope so easy to follow. Numbered procedure should correspond with numbered corrective action.

Q - What is an SSOP?

A - Sanitation Standard Operating Procedures — SSOPs — are the specific, written procedures necessary to ensure sanitary conditions in the food plant. They include written steps for cleaning and sanitizing to prevent product adulteration. SSOPs serve primarily to guide and orientate supervisors, management, regulators, and auditors, not necessarily the employees. An SSOP is a fundamental part of a Food Safety Plan. It may be a stand-along procedure or may be a Prerequisite Program (PP). It shall be updated whenever there is a change in processes or chemicals used. It should be reviewed annually with the Food Safety Plan.

  • An SSOP may written for
  • A piece of equipment
  • Several pieces of equipment in a process
  • An environmental area
  • As a Master Sanitation Plan for the whole facility.

Q. When does my HACCP certificate expire?

A - There is no government (FDA/USDA) regulation regarding time, but industry practice likes to see some food safety training every 3 years. If you have HACCP training, and it’s been 3 years, you might take a different food safety training that complements your work. If there are new updates, such as the FSMA rules that apply to your job, then its recommended to keep up with relevant training. All of the GFSI programs (i.e SQF, PrimusGFS, BRC, etc.) does require HACCP training every 5 years.

Q. Do Liquor companies have to comply with FSMA’s Preventive Controls rule?

A - Manufacturers (distillers) of alcoholic beverages are exempt from this rule. Unless you are processing, manufacturing, packaging food for human consumption this FDA regulatory requirement does not apply. However, if you are diverting your edible waste to animal feed operations, your company may be affected by FSMA.

The FDA and Worldwide Current Good Manufacturing Practices and Quality System Requirements Guidebook for Finished Pharmaceuticals

This guidance book is meant as a resource to manufacturers of pharmaceuticals, providing up-to-date information concerning required and recommended quality system practices. It should be used as a companion to the regulations/standards themselves and texts on the specific processes and activities contained within the QMS.

This book includes chapters on US current Good Manufacturing Practice (GMP) international GMP global GMP guides and harmonization detailed analysis of the requirements and guidances missing subparts what inspectors are looking for and the price of noncompliance. It also includes an appendix with two tabulated comparisons: the first compares US, European-PIC/S, Canadian, and WHO cGMPs, while the second compares US cGMPs with effective quality system elements.

The companion CD contains cGMP regulations for sterile products produced by aseptic processing it also includes updated data of statistical enforcement by the FDA, both domestically and abroad a detailed glossary and dozens of FDA guidance documents as well as international regulations (EU and Canada) and harmonization documents (WHO, PIC/S, and ICH). A very comprehensive checklist for a cGMP audit that is based on risk management criteria is also included. Finally, a comprehensive GMP exam is also included.

Good Manufacturing Practice (GMP) Resources

Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

GMP covers all aspects of production from the starting materials, premises, and equipment to the training and personal hygiene of staff. Detailed written procedures are essential for each process that could affect the quality of the finished product. There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process - every time a product is made.

GMP Resources

Training Options

Classroom Training

Online Training

USFDA's Systems-Based GMP Inspection Approach

GMP compliance is widely-accepted as the best way to conduct business, putting product quality first. Representing the “original” GMP Institute, ISPE’s GMP courses combine a convenient format with an effective, interactive learning experience. To maximize and customize your professional development. Complete each of the individual US FDA's GMP Inspection Approach online courses for an overview of all the Systems.

Basics of Sanitation & Current Good Manufacturing Practices

This course provides basic information about sanitation for food plants. The course walks through the principles of sanitation, sanitation chemicals, employee practices and other related topics. The course is specifically targeted to sanitation line workers.


Fee: $100 includes materials, certificate of attendance, refreshments and lunch.
Event website with registration link:

Location & Dates

Walter Clore Wine and Culinary Center
2140A Wine Country Rd
Prosser, WA 99350
(509) 494-7000
Training is limited to 50 people


Day 1
7:30am – 8:00am Check-in or Onsite Registration
8:00am – 8:10am Introductions & Kick-off
8:10am – 8:30am Overview of the Course and Importance of Sanitation in Food Safety
8:30am – 9:20am Overview of the cGMPs
9:20am – 9:30am Coffee Break
9:30am – 10:30am Basics of Food Microbiology
10:30am – 11:30am Personnel: Health & Hygiene
11:30am – 12:30pm Lunch Break – Provided
12:30pm – 1:30pm Basic Sanitizers
1:30pm – 2:30pm Equipment and Utensils Cleaning & Sanitary Design
2:30pm – 2:45pm Coffee Break
2:45pm – 3:45pm Basic Cleaning and Sanitation
3:45pm – 4:45pm Building Sanitation Procedures (SSOP)
Day 2
8:00am – 9:30am Basic CIP & COP
9:30am – 10:30am Allergen Management
10:30am – 10:45am Coffee Break
10:45am – 11:45am Sanitation Chemical Titration Testing – Best Practices
11:45am – 12:30pm Lunch Break – Provided
12:30pm – 1:30pm Stainless Steel Care & Protection
1:30pm – 2:30pm Warehousing, Storage, Raw Materials and Finished Products
2:30pm – 2:40pm Coffee Break
2:40pm – 3:40pm Hand Washing
3:40pm – 4:00pm Cougar Gold Cheese Drawings, Evaluations and Attendance Certificates.

* Program subject to change


Don Jones, FOAM-iT
Girish Ganjyal, Washington State University Extension

Watch the video: Good Manufacturing Practices GMP. Its Principle. GMP Vs CGMP. FSO (August 2022).