Quality in the Pharmaceutical Industry- A Literature Review

Abstract

Objectives
The aim of this study is to:
a.Highlight the most important guidelines and practices of quality in the pharmaceutical industry.b.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.

Design
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:
a.Research theme 1: Guidelines of the pharmaceutical quality.b.Research theme 2: General practices recently applied in the pharmaceutical industry.

Main outcome measures
The following guidelines were identified and reviewed: WHO guidelines, FDA guidelines, EU guidelines & 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 & HACCP.

Results
Upon reviewing the previously highlighted guidelines and the practices that are widely applied in the pharmaceutical industry, it was noticed that there is a 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.

Conclusions
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.

Full text

Accepted Manuscript
Review
Quality in the Pharmaceutical Industry- A Literature Review
Reham M. Haleem, Maissa Y. Salem, Faten A. Fatahallah, Laila E. Abdelfattah
PII: S1319-0164(13)00111-4
DOI: http://dx.doi.org/10.1016/j.jsps.2013.11.004
Reference: SPJ 253
To appear in: Saudi Pharmaceutical Journal
Received Date: 14 August 2013
Accepted Date: 10 November 2013
Please cite this article as: Haleem, R.M., Salem, M.Y., Fatahallah, F.A., Abdelfattah, L.E., Quality in the
Pharmaceutical Industry- A Literature Review, Saudi Pharmaceutical Journal (2013), doi: http://dx.doi.org/
10.1016/j.jsps.2013.11.004
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Title page:
Title: Quality in the Pharmaceutical Industry- A Literature Review
The authors’ full names qualifications, affiliations, departments, and addresses:
Reham M. Haleem1, Maissa Y. Salem2, Faten A. Fatahallah3, Laila E. Abdelfattah4
The e-mail address, telephone and fax numbers of the corresponding author:
E-mail address: rehamhaleem@hotmail.com
Telephone: 00966565464776
Key words:
Quality, pharmaceutical industry, GXPs
1 The National Organization for Research and Control of Biologicals, Cairo, Egypt
2 Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
3 The National Organization for Research and Control of Biologicals, Cairo, Egypt
4 Faculty of Pharmacy, Misr University for Science and Technology, 6th of October city, Egypt

1. Introduction:
The 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 & Webb 2003). 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 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 & Bruttin 2001). This is
followed by the identified research themes and their development. Finally, managerial
implications are discussed.

2. Methods:
A search was made of the following databases: WHO, FDA, ICH, 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.
They included:
• 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.
1.1. Research theme 1: Guidelines of the pharmaceutical quality:
The most important guidelines that are widely applied in the pharmaceutical industry are:
1.1.1. WHO guidelines
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
And 7 annexes:
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
1.1.2. FDA guidelines
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).
The most important guidelines are Code of Federal Regulation 210 & 211.
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 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).
1.1.3. EU guidelines
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
1.1.4. ICH guidelines
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.

1.2. Research theme 2: general practices recently applied in the pharmaceutical
industry:
1.2.1. Quality risk management
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).
1.2.2. Quality by design
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 2003).
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 2003).
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 2003).
1.2.3. Corrective action and preventive actions

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):
•
••
• Identify the problem.
•
••
• Evaluate its magnitude, which includes assessing risk.
•
••
• Investigate and assign responsibility.
•
••
• Analyze and document the root cause of the problem.
For example a new corrective action tracking system had helped Alcon Laboratories Inc. unite its
many corrective and preventive action systems worldwide resulting in faster time of closure on
corrective action, both access and speed to information is much greater and finally quality
professionals are able to focus on more important issues (Davis 2003).
1.2.4. Process capability analysis
Process capability is the comparison of the “Voice of the Customer” (VOC) with the “Voice of
the Process” (VOP). VOC, which is built on customer requirements, is defined by the
specification limits of the process, which are fixed, while VOP is defined by control limits,
which are based on performance data and vary over time (Tarpley 2004).
Metrics such as capability index namely Cp & Cpk were developed several years ago to calculate
this comparison between control and specification limits (Tarpley 2004).
The capability index a ratio that compares process spread to tolerance spread and results in a
single number. It is a management tool which is used to compare process performance. (Ruth II
2005).
1.2.5.Six Sigma
Harry and Schroeder (2000) define Six Sigma as “…a business process that enables companies
to increase profits dramatically by streamlining operations, improving quality, and eliminating

defects or mistakes in everything a company does….” It can help an organization reduce defects
and improve profitability using several basic tenets (Harry and Schroeder 2000; Johnson and
Swisher 2003; Pande, Neuman, and Cavanagh 2000; Williams 2003). (Goeke & Offodile 2005)
Six Sigma Projects are based on DMAIC model. (Stamatis 2002)
The DMAIC model is the generic model of six sigma methodology. It is an acronym that stands
for; Define, Measure, Analyze, Improve and Control. Sometimes this model includes recognize
as an awareness item to the model. Each of the components addresses a different aspect of the
overall improvement and breakthrough strategy (Stamatis 2002).
The pharmaceutical industry sigma level is from 2 to 3; this result in a 25-35 % defects. (Hussain
2005)
An example of the pharmaceutical firms that adopted the methodology of Six Sigma is
AstraZeneca where the operations and quality staff were trained to apply DMAIC principles
every day, to measure and improve performance through cross-functional “continuous
improvement” (CI) teams (Shanley 2005).
Two years ago, at Westborough, Massachusetts, cross-functional CI teams involving QA,
engineering and operations applied DMAIC principles to solve a major capacity problem for a
key product. The teams discovered wasteful processes, effectively adding 20 million extra units
of capacity per year. Where a capital investment of less than $100,000 led to $60 million to $70
million in revenue gains, without hiring new staff as Ron Matthews, vice president of
manufacturing and supply chain at the company, said (Shanley 2005).
1.2.6. Process analytical technologies
Process analytical technologies (PAT); play a key role in enabling “quality by design” and
scientific aspect of manufacturing. PAT main aim is to understand and control the manufacturing
process through the application of integrated chemical, physical, microbiological, mathematical
and risk analysis methods. PAT has been applied in non-Pharma industries for many years,
yielding cost savings and manufacturing efficiencies. (Fraser 2005)
The implementation of Process Analytical Technology (PAT) is bringing lots of benefits and
improvements for many pharmaceutical processes. The benefits are lower production cycle
times, improved manufacturing efficiency, reduced rejects and increased production operating
time (Rockwell Automation 2004).

Within Pharmaceutical industry, there have been a number of successful PAT-based
comparability protocol submissions, ranging from single-unit operation application at
GlaxoSmithKline to a more all-icluding application covering both drug substance and drug
product at Sanofi-Aventis (Shanley 2005).
1.2.7. Lean manufacturing
Japanese manufacturers re-building after the Second World War were facing declining human,
material, and financial resources. These circumstances led to the development of new, lower
cost, manufacturing practices. Early Japanese leaders such as the Toyota Motor Company's Eiji
Toyoda, Taiichi Ohno, and Shingeo Shingo developed a disciplined, process-focused production
system now known as the "Toyota Production System", or "lean production." The objective of
this system was to minimize the consumption of resources that added no value to a product
(Womack et al 1990).
Lean manufacturing is about eliminating waste across an entire company and focusing on the big
picture through learning how to do more with less (Nystuen 2002).
Lean means putting the right things in the right place at the right time the first time while
minimizing waste and being open to change. This leads to less waste, less design time, fewer
organizational layers, and fewer suppliers with more employee empowerment, more flexibility
and capability, more productivity, more customer satisfaction and without a doubt, more long-
term competitive success. Lean principles incorporated in the workplace today can spell business
survival for the future (Nave 2002).
In AstraZeneca; rather than being submerged into Lean, the company launched a limited
initiative at its global facilities in 2002 which is the Pull Manufacturing; this initiative required
that the company’s manufacturing teams shift their focus from output to customer alignment and
service. Also, the initiative has lead to reduction in the cycle time. In one case, it allowed lead
time for a key $1.5-billion-per year product to be reduced by 25% during a period when demand
for the drug was increasing by 30% (Shanley 2005).
Eli Lilly had suffered Factory losses – Process barely capable with some nonconformance and
Variability in product quality, the application of lean lead to system improvement and cost
savings as shown in the following table 2 (Mohan 2006).
(Insert table 1 here)
1.2.8.Total quality management

Total quality management (TQM) is a concept rather than a technique. It is a philosophy that
stresses a systematic, integrated, and consistent perspective that would involve everyone and
everything in the organization. (Isaac et al 2004)
TQM is a management philosophy that builds a customer driven, learning organization that s
devoted to total customer satisfaction through continuous improvement in the effectiveness and
efficiency of the organization and its corresponding processes (Corrigan 1995).
TQM is widely known for improving quality and other performances such as productivity, profit,
market share, and competitive edge of organizations of various types (Sun 2000) (Isaac et al
2004).
1.2.9.ISO series
ISO 9000 series
ISO 9000 is concerned with "quality management". This means what the organization does to
increase customer satisfaction through meeting customer and regulatory requirements and
continually improving its performance (ISO 9000 and 14001 in brief 2009).
ISO 14000
ISO 14000 is an environmental management system, describes the requirements for an
organization's environmental management system and can be used for certification/registration
and/or self declaration of an organization's environmental management system (ISO
14001:2004).
This means what the organization does to (ISO 9000 and14001 in brief 2009):
• Minimize harmful effects on the environment caused by its activities.
• Achieve continual improvement of its environmental performance.
ISO 17025
It gives the general requirements for the competence of testing and calibration laboratories
(ISO/IEC 17025:2005).
A specific version of this standard for Medical Laboratories has been developed; ISO
15189:2003 then ISO 15189:2007 was published on 19th April 2007 (ISO 15189:2007).
Through the accreditation process; the testing laboratory reaches the status of an independent
institution (Mettler-Toledo GmbH 2003).
1.2.10. HACCP

The Hazard Analysis and Critical Control Point (HACCP) methodology was known to be a
safety management system used in the food industry. Their main aim is to prevent known
hazards and to reduce the risks that they will cause at specific points in the food chain (Annex 7;
WHO TRS no 908, 2003).
Procedures, including GMP, address operational conditions and provide the basis for HACCP.
HACCP is a systematic method for the identification, assessment and control of safety hazards.
The hazards are classified to biological, chemical, or physical agents or operations that might
cause illness or injury if not controlled. In the manufacture of pharmaceuticals, this includes the
manufacture of certain antibiotics, hormones, cytotoxic substances or other highly active
pharmaceuticals. Together with operations such as fluid bed drying, granulation is an example of
hazard unit operations. The use of inflammable solvents (solutions) and certain laboratory
operations may also produce hazards (Annex 7; WHO TRS no 908, 2003).
The HACCP system is based on seven principles (Annex 7; WHO TRS no 908, 2003):
•
••
• Conduct a hazard analysis.
•
••
• Determine the critical control points (CCPs).
•
••
• Establish target levels and critical limit(s).
•
••
• Establish a system to monitor the CCPs.
•
••
• Establish the corrective action to be taken when monitoring indicates that a particular
CCP is not under control.
•
••
• Establish procedures to verify that the HACCP system is working effectively.
•
••
• Establish documentation concerning all procedures and keep records appropriate to these
principles and their application.
3. Results:
Upon reviewing the previously highlighted guidelines and the practices that are widely applied in
the pharmaceutical industry, it was noticed that there is a 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.
4. Discussions:

It is recommended that the literature would invest more in the area of application and
significance of guidelines and practices.
Also, there are some new practices that are recently applied to the pharmaceutical industry
though they are widely applied in non pharmaceutical industries, such as: the lean
manufacturing; the Six Sigma; the total quality management. Both managers at the
pharmaceutical industry and literature should focus on the adoption of such practices into the
pharmaceutical industry making use of the previous research in the non-pharmaceutical industry
application. New case studies should be done to prove the feasibility of such practices.

5. References:
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((Accessed at September 26, 2006)
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(Accessed at September 26, 2006)
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Elsevier Editorial System(tm) for Saudi Pharmaceutical Journal
Manuscript Draft
Manuscript Number: SPJ-D-13-00526
Title: Quality in the Pharmaceutical Industry- A Literature Review
Article Type: Review Article
Corresponding Author: Mrs. Reham haleem,
Corresponding Author's Institution:
First Author: Reham M haleem
Order of Authors: Reham M haleem; Reham haleem; Maissa Y Salem; Faten A Fatahallah; Laila E
Abdelfattah
Abstract: Objectives:
The aim of this study is to:
a. Highlight the most important guidelines and practices of quality in the pharmaceutical
industry.
b. 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.
Design:
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:
a. Research theme 1: Guidelines of the pharmaceutical quality.
b. Research theme 2: General practices recently applied in the pharmaceutical industry.
Main outcome measures:
The following guidelines were identified and reviewed: WHO guidelines, FDA guidelines, EU guidelines
& 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 & HACCP.
Results:
Upon reviewing the previously highlighted guidelines and the practices that are widely applied in the
pharmaceutical industry, it was noticed that there is a 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.
Conclusions:
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.