Good manufacturing practice

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Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, [1] cosmetics, [2] pharmaceutical products, [3] dietary supplements, [4] and medical devices. [5] These guidelines provide minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use.

Contents

Good Manufacturing Practice emerged in response to serious incidents of harm caused by contaminated, adulterated, or improperly manufactured products. Major incidents include: deaths from Elixir Sulfanilamide in 1937, thalidomide-induced birthdefects 1957-1961, poliomyelitis infections from improperly prepared vaccines in 1955, and Dalkon Shield-induced septicemia in the 1970's.

These incidents resulted in hundreds of deaths, infections, and birth defects. Complete timelines show the emergence of Good Manufacturing Practices alongside these incidents, starting from 1938 in the US and 1970s internationally. [6]

The rules that govern each industry may differ significantly; however, the main purpose of GMP is always to prevent harm from occurring to the end user. [2] Additional tenets include ensuring the end product is free from contamination, that it is consistent in its manufacture, that its manufacture has been well documented, that personnel are well trained, and that the product has been checked for quality more than just at the end phase. [2] GMP is typically ensured through the effective use of a quality management system (QMS). [1] : "The Basis for GMP",   [2]

Good manufacturing practice, along with good agricultural practice, good laboratory practice and good clinical practice, are overseen by regulatory agencies in the United Kingdom, United States, Canada, various European countries, China, India and other countries.

High-level details

Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality assurance in order to ensure that a manufactured product is safe for human consumption or use. Many countries have legislated that manufacturers follow GMP procedures and create their own GMP guidelines that correspond with their legislation.

All guidelines follow a few basic principles: [2] [7]

Good manufacturing practice is recommended with the goal of safeguarding the health of consumers and patients as well as producing quality products. In the United States, a food or drug may be deemed "adulterated" if it has passed all of the specifications tests but is found to be manufactured in a facility or condition which violates or does not comply with current good manufacturing guideline.

GMP standards are not prescriptive instructions on how to manufacture products. They are a series of performance based requirements that must be met during manufacturing. [10] When a company is setting up its quality program and manufacturing process, there may be many ways it can fulfill GMP requirements. It is the company's responsibility to determine the most effective and efficient quality process that both meets business and regulatory needs. [1] : "Decision Makers' Summary",   [2]

Regulatory agencies have recently begun to look at more fundamental quality metrics of manufacturers than just compliance with basic GMP regulations. US-FDA has found that manufacturers who have implemented quality metrics programs [11] gain a deeper insight into employee behaviors that impact product quality.

In its Guidance for Industry "Data Integrity and Compliance With Drug CGMP" US-FDA states “it is the role of management with executive responsibility to create a quality culture where employees understand that [[data integrity [12] ]] is an organizational core value and employees are encouraged to identify and promptly report data integrity issues.” [13] Australia's Therapeutic Goods Administration has said that recent data integrity failures have raised questions about the role of quality culture in driving behaviors. [14] In addition, non-governmental organizations such as the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral Drug Association (PDA) have developed information and resources to help pharmaceutical companies better understand why quality culture is important and how to assess the current situation within a site or organization. [15]

Guideline versions

GMP is enforced in the United States by the U.S. Food and Drug Administration (FDA), under Title 21 CFR. The regulations use the phrase "current good manufacturing practices" (CGMP) to describe these guidelines. [16] [17] [18] [19] Courts may theoretically hold that a product is adulterated even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards. [20] However, since June 2007, a different set of CGMP requirements have applied to all manufacturers of dietary supplements, with additional supporting guidance issued in 2010. [4] Additionally, in the U.S., medical device manufacturers must follow what are called "quality system regulations" which are deliberately harmonized with ISO requirements, not necessarily CGMPs. [18]

The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over 100 countries worldwide, primarily in the developing world. [3] The European Union's GMP (EU GMP) enforces similar requirements to WHO GMP, as does the FDA's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Saudi Arabia, Singapore, Philippines], Vietnam and others having highly developed/sophisticated GMP requirements. [21] In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide," which is named so because of the color of its cover; it is officially known as Rules and Guidance for Pharmaceutical Manufacturers and Distributors. [22]

Since the 1999 publication of Good Manufacturing Practice for Active Pharmaceutical Ingredients, by the International Conference on Harmonization (ICH), GMPs now apply in those countries and trade groupings that are signatories to ICH (the EU, Japan and the U.S.), and applies in other countries (e.g., Australia, Canada, Singapore) which adopt ICH guidelines for the manufacture and testing of active raw materials. [21]

Enforcement

Within the European Union GMP inspections are performed by National Regulatory Agencies. GMP inspections are performed in Canada by the Health Products and Food Branch Inspectorate; [23] in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA); [24] in the Republic of Korea (South Korea) by the Ministry of Food and Drug Safety (MFDS); [25] in Australia by the Therapeutic Goods Administration (TGA); [26] in Bangladesh by the Directorate General of Drug Administration (DGDA); [27] in South Africa by the Medicines Control Council (MCC); [28] in Brazil by the National Health Surveillance Agency (ANVISA); [29] in India by state Food and Drugs Administrations (FDA), reporting to the Central Drugs Standard Control Organization; [30] in Pakistan by the Drug Regulatory Authority of Pakistan; [31] in Nigeria by NAFDAC; [32] and by similar national organizations worldwide. Each of the inspectorates carries out routine GMP inspections to ensure that drug products are produced safely and correctly. Additionally, many countries perform pre-approval inspections (PAI) for GMP compliance prior to the approval of a new drug for marketing.

CGMP inspections

Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many European nations) are authorized to conduct unannounced inspections, though some are scheduled. [16] [22] [25] [26] [27] [28] [30] [31] [32] FDA routine domestic inspections are usually unannounced, but must be conducted according to 704(a) of the Food, Drug and Cosmetic Act (21 USCS § 374), which requires that they are performed at a "reasonable time". Courts have held that any time the firm is open for business is a reasonable time for an inspection. [33]

Other good practices

Other good-practice systems, along the same lines as GMP, exist:

Collectively, these and other good-practice requirements are referred to as "GxP" requirements, all of which follow similar philosophies. Other examples include good guidance practice and good tissue practice.

See also

Related Research Articles

<span class="mw-page-title-main">Food and Drug Administration</span> United States federal agency

The United States Food and Drug Administration is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, caffeine products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed and veterinary products.

A quality management system (QMS) is a collection of business processes focused on consistently meeting customer requirements and enhancing their satisfaction. It is aligned with an organization's purpose and strategic direction. It is expressed as the organizational goals and aspirations, policies, processes, documented information, and resources needed to implement and maintain it. Early quality management systems emphasized predictable outcomes of an industrial product production line, using simple statistics and random sampling. By the 20th century, labor inputs were typically the most costly inputs in most industrialized societies, so focus shifted to team cooperation and dynamics, especially the early signaling of problems via a continual improvement cycle. In the 21st century, QMS has tended to converge with sustainability and transparency initiatives, as both investor and customer satisfaction and perceived quality are increasingly tied to these factors. Of QMS regimes, the ISO 9000 family of standards is probably the most widely implemented worldwide – the ISO 19011 audit regime applies to both and deals with quality and sustainability and their integration.

<span class="mw-page-title-main">Hazard analysis and critical control points</span> Systematic preventive approach to food safety

Hazard analysis and critical control points, or HACCP, is a systematic preventive approach to food safety from biological, chemical, and physical hazards in production processes that can cause the finished product to be unsafe and designs measures to reduce these risks to a safe level. In this manner, HACCP attempts to avoid hazards rather than attempting to inspect finished products for the effects of those hazards. The HACCP system can be used at all stages of a food chain, from food production and preparation processes including packaging, distribution, etc. The Food and Drug Administration (FDA) and the United States Department of Agriculture (USDA) require mandatory HACCP programs for juice and meat as an effective approach to food safety and protecting public health. Meat HACCP systems are regulated by the USDA, while seafood and juice are regulated by the FDA. All other food companies in the United States that are required to register with the FDA under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, as well as firms outside the US that export food to the US, are transitioning to mandatory hazard analysis and risk-based preventive controls (HARPC) plans.

Ranbaxy Laboratories Limited was an Indian multinational pharmaceutical company that was incorporated in India in 1961 and remained an entity until 2014. The company went public in 1973. Ownership of Ranbaxy changed twice over the course of its history.

Computerized system validation (CSV) is the process of testing/validating/qualifying a regulated computerized system to ensure that it does exactly what it is designed to do in a consistent and reproducible manner that is as safe, secure and reliable as paper-based records. This is widely used in the Pharmaceutical, Life Sciences and BioTech industries and is a cousin of Software Testing but with a more formal and documented approach. The validation process begins with validation planning, system requirements definition, testing and verification activities, and validation reporting. The system lifecycle then enters the operational phase and continues until system retirement and retention of system data based on regulatory rules.

<span class="mw-page-title-main">Bioequivalence</span> Similarity between preparations of a drug

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.

GxP is a general abbreviation for the "good practice" quality guidelines and regulations. The "x" stands for the various fields, including the pharmaceutical and food industries, for example good agricultural practice, or GAP.

The Principles of Good Laboratory Practice (GLP) establish rules and criteria for a quality system that oversees the organizational processes and conditions in which non-clinical health and environmental safety studies are planned, conducted, monitored, recorded, reported, and archived. These principles apply to the non-clinical safety testing of substances found in various products to ensure the quality and integrity of the safety data submitted to regulatory authorities globally.

The process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in testing and then production maintains the desired level of compliance at all stages. In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results. The desired results are established in terms of specifications for outcome of the process. Qualification of systems and equipment is therefore a part of the process of validation. Validation is a requirement of food, drug and pharmaceutical regulating agencies such as the US FDA and their good manufacturing practices guidelines. Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following:

Good engineering practice (GEP) is engineering and technical activities that ensure that a company manufactures products of the required quality as expected. Good engineering practices are to ensure that the development and/or manufacturing effort consistently generates deliverables that support the requirements for qualification or validation. Good engineering practices are applied to all industries that require engineering.

Good automated manufacturing practice (GAMP) is both a technical subcommittee of the International Society for Pharmaceutical Engineering (ISPE) and a set of guidelines for manufacturers and users of automated systems in the pharmaceutical industry. More specifically, the ISPE's guide The Good Automated Manufacturing Practice (GAMP) Guide for Validation of Automated Systems in Pharmaceutical Manufacture describes a set of principles and procedures that help ensure that pharmaceutical products have the required quality. One of the core principles of GAMP is that quality cannot be tested into a batch of product but must be built into each stage of the manufacturing process. As a result, GAMP covers all aspects of production; from the raw materials, facility and equipment to the training and hygiene of staff. Standard operating procedures (SOPs) are essential for processes that can affect the quality of the finished product.

Verification and validation are independent procedures that are used together for checking that a product, service, or system meets requirements and specifications and that it fulfills its intended purpose. These are critical components of a quality management system such as ISO 9000. The words "verification" and "validation" are sometimes preceded with "independent", indicating that the verification and validation is to be performed by a disinterested third party. "Independent verification and validation" can be abbreviated as "IV&V".

Quality by design (QbD) is a concept first outlined by quality expert Joseph M. Juran in publications, most notably Juran on Quality by Design. Designing for quality and innovation is one of the three universal processes of the Juran Trilogy, in which Juran describes what is required to achieve breakthroughs in new products, services, and processes. Juran believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned.

Good documentation practice is a term in the pharmaceutical and medical device industries to describe standards by which documents are created and maintained. While some GDocP standards are codified by various competent authorities, others are not but are considered cGMP. Some competent authorities release or adopt guidelines, and they may include non-codified GDocP expectations. While not law, authorities will inspect against these guidelines and cGMP expectations in addition to the legal requirements and make comments or observations if departures are seen. In the past years, the application of GDocP is also expanding to cosmetic industry, excipient and ingredient manufacturers.

The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, Sec. 704 "Factory Inspection". Form FDA 483, "Inspectional Observations", is a form used by the FDA to document and communicate concerns discovered during these inspections. Also referred to as "Form 483" or merely "483", it states thereon that it

... lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance

An FDA warning letter is an official message from the United States Food and Drug Administration (FDA) to a manufacturer or other organization that has violated some rule in a federally regulated activity.

Process validation is the analysis of data gathered throughout the design and manufacturing of a product in order to confirm that the process can reliably output products of a determined standard. Regulatory authorities like EMA and FDA have published guidelines relating to process validation. The purpose of process validation is to ensure varied inputs lead to consistent and high quality outputs. Process validation is an ongoing process that must be frequently adapted as manufacturing feedback is gathered. End-to-end validation of production processes is essential in determining product quality because quality cannot always be determined by finished-product inspection. Process validation can be broken down into 3 steps: process design, process qualification, and continued process verification.

Guidances for statistics in regulatory affairs refers to specific documents or guidelines that provide instructions, recommendations, and standards pertaining to the application of statistical methodologies and practices within the regulatory framework of industries such as pharmaceuticals and medical devices. These guidances serve as a reference for statisticians, researchers, and professionals involved in designing, conducting, analyzing, and reporting studies and trials in compliance with regulatory requirements. These documents embody the prevailing perspectives of regulatory agencies on specific subjects. It is worth noting that in the United States, the term "Guidances" is used, while in Europe, the term "Guidelines" is employed.

The distribution of medications has special drug safety and security considerations. Some drugs require cold chain management in their distribution.

References

  1. 1 2 3 Institute of Food Science & Technology (2013). Food and Drink - Good Manufacturing Practice - A Guide to its responsible management. London: Wiley-Blackwell. ISBN   9781118318232 – via Google Books (Preview).
  2. 1 2 3 4 5 6 Moore, Iain (2009). "Chapter 5: Manufacturing Cosmetic Ingredients According to Good Manufacturing Principles". In Lintner, Karl (ed.). Global Regulatory Issues for the Cosmetic Industry. Vol. 2. Norwich, New York: William Andrew. pp. 79–92. ISBN   9780815519645 – via Google Books (Preview).
  3. 1 2 Nally, J.D., ed. (2007). Good Manufacturing Practices for Pharmaceuticals (6th ed.). CRC Press. p. 424. ISBN   9781420020939.
  4. 1 2 "Guidance for Industry: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements; Small Entity Compliance Guide". U.S. Food and Drug and Administration. 12 November 2017. Retrieved 2 February 2018.
  5. ↑ Ramakrishna, S.; Tian, L.; Wang, C.; et al., eds. (2015). "Chapter 3.: Quality management systems for medical device manufacture". Medical Devices: Regulations, Standards and Practices. Woodhead Publishing Series in Biomaterials. Vol. 103. Elsevier. pp. 49–64. ISBN   9780081002919.
  6. ↑ "Why does Good Manufacturing Practice exist?". SystemValidation. Retrieved 29 September 2024.
  7. ↑ World Health Organization (2007). "Chapter 1: WHO good manufacturing practices: Main principles for pharmaceutical products". Quality Assurance of Pharmaceuticals: A compendium of guidelines and related materials - Good manufacturing practices and inspection. Vol. 2 (2nd updated ed.). WHO Press. pp. 17–18. ISBN   9789241547086.
  8. ↑ "What is Validation?". SystemValidation. Retrieved 29 September 2024.
  9. ↑ "What is Validation?". SystemValidation. Retrieved 29 September 2024.
  10. ↑ "Performance-Based Safety Regulation | Policy Studies". www.trb.org. Retrieved 2020-12-28.
  11. ↑ Center for Drug Evaluation and Research (2019-12-20). "Frequently Asked Questions regarding the Quality Metrics Site Visit and Feedback Programs". FDA.
  12. ↑ "Data Integrity & Audit Trails". SystemValidation. Retrieved 29 September 2024.
  13. ↑ US Food and Drug Administration (2018). "Data Integrity and Compliance With Drug CGMP Questions and Answers Guidance for Industry". US-Food and Drug Administration. Retrieved October 9, 2021.
  14. ↑ Australian Government Department of Health Therapeutic Goods Administration (2018-08-09). "Presentation: Driving a GMP / Quality Culture to provide supporting evidence of better business outcomes". Therapeutic Goods Administration (TGA). Retrieved 2020-12-10.[ permanent dead link ]
  15. ↑ Frederick, Tami (2019). "ISPE – PDA Guide to Improving Quality Culture in Pharmaceutical Manufacturing Facilities" (PDF). International Society for Pharmaceutical Engineering. Retrieved 2020-12-09.
  16. 1 2 "Facts About the Current Good Manufacturing Practices (CGMPs)". U.S. Food and Drug Administration. 6 October 2017. Retrieved 2 February 2018.
  17. ↑ "Current Good Manufacturing Practices (CGMPs)". U.S. Food and Drug Administration. 27 December 2017. Retrieved 2 February 2018.
  18. 1 2 "Quality System (QS) Regulation/Medical Device Good Manufacturing Practices". U.S. Food and Drug Administration. 2 February 2018. Retrieved 2 February 2018.
  19. ↑ "Draft Guidance for Industry: Cosmetic Good Manufacturing Practices". U.S. Food and Drug Administration. 3 November 2017. Retrieved 2 February 2018.
  20. ↑ "US CFR Title 21 §210.1(b) Status of current good manufacturing practice regulations". Electronic Code of Federal Regulations. Retrieved 24 August 2017.
  21. 1 2 Cartwright, A.C.; Matthews, B.R., eds. (2010). "Preface". International Pharmaceutical Product Registration (2nd ed.). CRC Press. pp. vi–x. ISBN   9781420081831.
  22. 1 2 Medicines and Healthcare products Regulatory Agency. "Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017". Pharmaceutical Press. Retrieved 2 February 2018.
  23. ↑ "Good Manufacturing Practices". Health Canada. Government of Canada. 27 February 2015. Retrieved 2 February 2018.
  24. ↑ Medicines and Healthcare products Regulatory Agency (20 October 2017). "Good manufacturing practice and good distribution practice". Gov.uk. Retrieved 2 February 2018.
  25. 1 2 Ministry of Food and Drug Safety (April 2017). "Guide to Drug Approval System in Korea" (PDF). National Institute of Food and Drug Safety Evaluation. Retrieved 2 February 2018.
  26. 1 2 "Good manufacturing practice - an overview". Department of Health, Therapeutic Goods Administration. 29 September 2017. Retrieved 2 February 2018.
  27. 1 2 Anisfeld, M.H.; Kim, E.M.; Aimiuwu, J.; Thumm, M. (May 2015). "Assessment of the Good Manufacturing Practices Inspection Program of the Bangladesh Directorate General of Drug Administration". World Health Organization. Archived from the original on April 29, 2017. Retrieved 2 February 2018.
  28. 1 2 "Guide to Good Manufacturing Practice for Medicines in South Africa" (PDF). Medicines Control Council. August 2010. Retrieved 2 February 2018.
  29. ↑ "Draft Technical Resolution nº 42, May 13th 2015" (PDF). World Trade Organization. 13 May 2015. Retrieved 2 February 2018.
  30. 1 2 "Updated list of WHO GMP Certified Manufacturing Units for Certificate of Pharmaceutical Products (COPP) in various States of India as on December 2016". Central Drugs Standard Control Organization. 10 June 2017. Archived from the original on 3 February 2018. Retrieved 2 February 2018.
  31. 1 2 "S.R.O. 1012(I)/2017" (PDF). The Gazette of Pakistan. Government of Pakistan. 9 October 2017. Archived from the original (PDF) on 2 February 2018. Retrieved 2 February 2018.
  32. 1 2 "GMP Guidelines". National Agency for Food and Drug Administration and Control. Archived from the original on 3 February 2018. Retrieved 2 February 2018.
  33. ↑ "Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection" (PDF). U.S. Food and Drug Administration. October 2014. Retrieved 2 February 2018.
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