This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
The aim of this study is to:
Highlight the most important guidelines and practices of quality in the pharmaceutical industry.Organize such guidelines and practices to create a guide to pave the way for other researchers who would like to dig deeper into these guidelines and practices.
A review was conducted of 102 publications; 56 publications were concerned with the pharmaceutical quality directly while 46 publications were concerned with the general quality practices. The content of those sources was analyzed and the following themes were identified:
Research theme 1: Guidelines of the pharmaceutical quality. Research theme 2: General practices recently applied in the pharmaceutical industry.The following guidelines were identified and reviewed: WHO guidelines, FDA guidelines, EU guidelines and ICH guidelines in the research theme I.
In research theme II; the following topics were identified and reviewed: quality risk management, quality by design, corrective actions and preventive actions, process capability analysis, Six Sigma, process analytical technology, lean manufacturing, total quality management, ISO series and HACCP.
Upon reviewing the previously highlighted guidelines and the practices that are widely applied in the pharmaceutical industry, it was noticed that there is an abundant number of papers and articles that explain the general guidelines and practices but the literature lack those describing application; case studies of the pharmaceutical factories applying those guidelines and significance of those guidelines and practices.
It is recommended that the literature would invest more in the area of application and significance of guidelines and practices. New case studies should be done to prove the feasibility of such practices.
Keywords: Quality, Pharmaceutical industry, GXPsThe quality in the pharmaceutical industry has become a very important topic. Since the world has gathered together to harmonize its practices and guides and the launching of the FDA current good manufacturing practices – the cGMP; for the 21st century – there has been a growing awareness for the significance of the quality of the pharmaceutical products (Woodcock, 2004). This awareness is represented through the appearance of several definitions defining exactly what the quality of the medicine should be (LEE and Webb, 2009). Many articles were written to demonstrate the special nature of the product-customer relationship of medicine and patients (Woodcock, 2004). Also the important role of governments was emphasized through the joint statement between the international pharmaceutical federation; FIP; and the international federation of pharmaceutical manufacturers associations; IFPMA; to ensure the safety of medicinal products in order to protect the patient (FIP Council, 1999), providing that the pharmaceutical industry is one of the most closely regulated industries for more than 50 years (Woodcock, 2004).
Since 2002, FDA began an initiative to address cGMP for the 21st century (Woodcock, 2004). This effort involved taking new looks at both the regulatory and industrial systems for insuring drug quality (Larson, 2006).
A literature review was conducted on the quality in the pharmaceutical industry, identifying 102 publications that focus on conceptual issues, methodological issues, or the application of different practices and/or guidelines applied in the pharmaceutical industries. The content of these sources was analyzed, and a number of themes were identified.
The literature review has two objectives concerned with the quality guidelines and practices of the pharmaceutical industry and the organization such as practices and guidelines to make a guide for others to use.
A research of this kind serves to integrate past research and can help current and future researchers, and practitioners employing the suitable guideline or practice to develop their methodological decisions in upgrading the industry.
This article introduced some issues regarding what is so special about pharmaceutical quality and different drivers of quality are then identified (Fraser, 2005; Dean and Bruttin, 2001). This is followed by the identified research themes and their development. Finally, managerial implications are discussed.
A search was made of the following databases: WHO, FDA, ICH, and EU to download their corresponding guidelines. Using the Google search engine; also a number of papers and articles were downloaded. Search words used were: pharmaceutical quality, quality and pharmaceutical industry. Papers that were not academic in nature were rejected (for example, those that did not provide reference citations).
The final sample consisted of 102 publications; 56 publications were related to the pharmaceutical quality directly while 46 publications were concerned with the general quality practices.
Two research themes could be identified in the articles studied in this literature review.
Guidelines of the pharmaceutical quality. General practices recently applied in the pharmaceutical industry.For each of these research themes the authors synthesize the main findings and offer suggestions for further research.
The most important guidelines that are widely applied in the pharmaceutical industry are:
WHO has published a handbook on the GMP in particular, entitled: Quality assurance of pharmaceuticals, a compendium of guidelines and related materials, Volume 2: good manufacturing practices and inspection (Quality Assurance of Pharmaceuticals, 2004).
It consists of 4 chapters:
Chapter 1: WHO GMP: main principles for pharmaceutical products. Chapter 2: Good manufacturing practices: starting materials. Chapter 3: Good manufacturing practices: specific pharmaceutical products. Chapter 4: Inspection. Annex 3: Radiopharmaceutical products. Annex 4: Good manufacturing practices for pharmaceutical products: main principles. Annex 5: Model Certificate of GMP. Annex 6: Sterile pharmaceutical products. Annex 6: Guidance on GMP inspection. Annex 7: Pre-approval inspection. Annex 8: Quality system requirements for national GMP inspectorates.Pharmaceutical manufacturers have just begun to understand and apply the FDA’s cGMPs for the 21st century: A Risk-Based Approach; the initiative outlines immediate, near and longer-term stages that FDA believes will take two years to be implemented (Larson 2004).
On the technical side, FDA states three concepts that will guide the reevaluation process: advances in risk management science, advances in quality management science and advances in pharmaceutical science and manufacturing technology (Larson, 2004).
21CFR Part 210: The regulations contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such a drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it claims to possess.
21CFR Part 211: The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.
The FDA has concluded that modern quality systems together with manufacturing processes and product knowledge, can handle many types of changes to facilities, equipment and processes without the need for regulatory submission (Fraser, 2005).
The core of European Union legislation in the pharmaceutical sector is gathered in Volume 1 and Volume 5 of the publication; “The rules governing medicinal products in the European Union”.
Volume 1 – EU pharmaceutical legislation for medicinal products for human use. Volume 5 – EU pharmaceutical legislation for medicinal products for veterinary use.The basic legislation is supported by a series of guidelines that are also published in the following volumes of “The rules governing medicinal products in the European Union”:
Volume 2 – Notice to applicants and regulatory guidelines for medicinal products for human use. Volume 3 – Scientific guidelines for medicinal products for human use.Volume 4 – Guidelines for good manufacturing practices for medicinal products for human and veterinary use.
Volume 6 – Notice to applicants and regulatory guidelines for medicinal products for veterinary use. Volume 7 – Scientific guidelines for medicinal products for veterinary use. Volume 8 – Maximum residue limits. Volume 9 – Guidelines for pharmacovigilance for medicinal products for human and veterinary use. Volume 10 – Guidelines for clinical trial.The International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) is a special project that gathers the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three different regions; to discuss scientific and technical aspects of product registration.
The objective of such harmonization is a more efficient use of human, animal and material resources, and the removal of any delay that is not essential in the global development and availability of new medicines while maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.
All products and all processes have an inherent element of risk (Griffith, 2004).
In an organization that is intending to apply an effective quality risk management approach, a clear definition of what is considered ”risk” should be agreed upon because of the too many stakeholders in the pharmaceutical industry and their corresponding diverse interests (ICH Q9, 2003).
The FDA has noticed that it needs to reorganize its procedures and processes to merge the use of risk management programs (RMP) within the agency and within the industries it regulates. Consequently, the FDA has started publishing position papers and guidelines on what it expects to see in an RMP (Griffith, 2004).
Risk management plans should be used to identify risk (Griffith 2004).
Quality Risk Management is defined as a method for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product through the product lifecycle where decisions can occur at any point in the process (ICH Q9, 2003).
In the guideline entitled Medical Device Use-Safety: incorporating human factors engineering into risk management; it clarifies how hazards related to medical device use should be directed during device development as part of the risk management process (CDRH, 2000).
ICH Q8 defines design space from the concept that quality cannot be tested into product but has to be built in by design (ICH Q8, 2005–2008).
Based on the ICH Q8; which concerns pharmaceutical development with targeting designing quality into the ingredients, formulation and manufacturing process to deliver the intended performance of the product. Design space is presented by the applicant and is subject to regulatory assessment and approval (ICH Q8, 2005–2008).
In these situations, opportunities exist to develop more flexible regulatory approaches.
The design and conduct of pharmaceutical development research should be consistent with their intended scientific purpose (ICH Q8, 2005–2008).
QMS nonconformities and other system deficiencies, including legal noncompliance, should be analyzed to detect patterns or trends. Identifying trends allows the manufacturer to anticipate and prevent future problems (EPA, 2009).
The organization should focus on correcting and preventing problems. Preventing problems is generally cheaper than fixing them after they occur. The organization should also start thinking about problems as opportunities to improve (EPA, 2009).
“Root cause analysis” is a process by which the manufacturer can identify causes and preventive actions (EPA, 2009).
In general, CAPA experts recommend that root-cause investigations follow a four-step process (Bartholomew, 2006):