Quality Assurance in Pharmaceutical Industry

Article Written By Mr. Piyush Tripathi

Quality Assurance in Pharmaceutical Industry

- Regulatory Norms, and QA Norms.
- QA implementation
- QA Focus
- QA upgrades

What is Quality Assurance?

Quality Assurance a “word of world”, a symbol and an assurance not only to the company but to an individual self as a reliable product identity, Quality assurance is most important and is always talked of but never explored. What is Quality Assurance? What does it do? What is its Importance? What Norms? What is the Use?. All these questions are always half way answered. With increasing globalization of commerce and trade, and the merging of pharmaceutical companies, are internationalizing pharmaceutical production. International pharmaceutical norms and standards are thus more important than ever before since they apply to as global tool and an ensure safety and quality of drug. WHO (WORLD HEALTH ORGANIZATION) plays and applies continuous development of international norms and standards, to scale and implement standard and practices.

For safety and quality guidelines many organizations are playing a lead roll to ensure pharmaceuticals are also been promoted through regional and international efforts to harmonize drug regulation such as those led by, ASEAN (Association of South-East Asian Nations), CAN (Andean Community), CADREAC (The Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries), the European Union, Gulf Cooperation Council (GCC), the International Conference on Harmonization (ICH), MERCOSUR (Southern Common Market) the Pan American Network on Drug Regulatory Harmonization (PANDRH) and the Southern African Development Community (SADC). These efforts are to be welcomed since international consensus on quality, safety and efficacy standards can speed up access to medicines.

Quality Assurance levels differ from country to country, not all countries have the same resource and capacity for implementation and agreements on drug regulation. Drug regulation step wise recommendation approach for achieving the highest possible level of medicine safety, regulation and quality assurance in each country is done by related authorities, experts and consultants. Authorities (WHO’S) role is to identify areas in which further guidance needs to be developed for preliminary and intermediate steps. Checklists based on test for detecting substandard and counterfeit drugs are just one example.

Advancement, modern technology and rapidly evolving science are creating problems for regulatory authorities everywhere. Training and specialization requirements for dealing with the increasing complexity of technological advanced products can be especially burdensome. Developing norms and standards for use in health technology and product development, “WHO” reduce this problem, while at the same time helping to minimize unnecessary duplication of scientific expertise and effort. Pharmaceutical industry is also bringing other safety issues like non-prescription medicines are becoming increasingly available to the general public in all countries, including though such channels as the Internet, monitoring their safety and quality are often lacking.

Quality Assurance In Pharma Industry:

In Pharma industry quality assurance is a broad concept covering all matters that collectively or individually influence the quality of drug or product. Quality assurance in pharmaceutical can be divided into four major areas:
1. Quality control
2. Production
3. Distribution and
4. Inspections.
Guidelines, norms and standards to promote quality assurance is an integral part of WHO’S constitution and has been endorsed and supported through numerous World Health Assembly resolutions, and more recently in those of the Revised Drug Strategy.

Guidelines, Norms, and standards

Quality assurance guidance for the respective divisions covers good manufacturing practices (GMP) Current Good Manufacturing Practices (cGMP), Quality assurance for regulatory approval; prequalification of medicines, laboratories and supply agencies; model certificates for quality assurance; quality control testing; new specification for inclusion in the basic test series and the international pharmacopoeia; and international chemical reference standards; the program on international nonproprietary names (INN) which is used to identify each pharmaceutical ingratiate or substance by a unique and universally accessible name. The need to scale up access to affordable quality medicines in developing countries has raised many challenges within the pharmaceutical world. These challenges are on top of the reality that among national regulatory authorities there is a variable capacity to interpret and apply existing norms and standards and guidelines on regulation quality control, nomenclature and classification of pharmaceuticals. WHO has strengthened and promoted global norms, standards and guidelines for the quality, safety and implication of medicine.


Accuracy Of Quality Assurance

QA primarily is metrics, or measurability. Process involves evaluation and testing to determine if the products meets specifications, such as performance measures. Results, involve delays in production until all rework or remediation steps have been undertaken. Cost related to products that do not meet minimum quality standards can be unacceptably high.

Steps For A Typical Quality Assurance Process

QA process has many scope and depth. The application of a process is often customized to the product process.

A typical process may include:

a. Test of previous Articles
b. Plan to improve
c. Design to include improvements and requirements
d. Manufacture with improvements
e. Review new item and improvements
f. Test of the new item

National Drug Regulatory Authorities (NDRAs) and pharmaceutical manufactures, as well as international bodies such as Global Fund to Fight AIDS, TB and Malaria (GFATM), AND UNICEF, all depend on the committee’s norms, standards and guidelines. These tools are also fundamental importance to such high profile initiatives as the UN prequalification program, the Global Malaria Programme and Stop TB. Originally mandated to develop The International Pharmacopoeia, the Committee has been seen its quality assurance role broaden and deepen significantly over the last 50 years. Convened annually, it addresses a range of subjects, from active and non-active pharmaceutical ingredients, to regulatory guidelines for marketing authorizations (registration) of medicines an effort that with such issues as stability testing, manufacturing variations and interchangeability. But whatever the subject, the aim remains constant: to promote quality assurance and quality control of pharmaceuticals.

The norms, standards and guidelines review by the committee are prepared through a rigorous consultative process involving WHO member States, National authorities and international agencies such as UNICEF. When applied, they form a basis of robust implementation of good manufacturing and distribution practices. They thus help avoid wasting public resources on medicines that are inefficient or even harmful. Providing sufficient resources for these normative activities is thus critical to sustaining vital public health programmes and by preventing duplication of efforts worldwide promotes cost effectiveness.

Available International Chemical Reference Substances (ICRS)

Chemical reference substances are an essential tool in a laboratory’s quality control testing of pharmaceuticals. They are used primarily to validate the test results obtained from a specific method, and are also used as primary standards to calibrate secondary standards. Following a complex procedure aligned with the WHO Guidelines on the Establishment, Maintenance and Distribution of Chemical Reference Substances, lists of these substances were adopted by the committee and are regularly updated to focus on essential medicines and medicines used in treating large populations, for which international quality requirements are often not publicly available. NDRAs and the quality control laboratories of pharmaceutical manufacturers use ICRS in physical and chemical test described in quality control specifications for medicine published in The International Pharmacopoeia.

WHO’s ICRS collection is developed, stored, monitored and distributed worldwide by the WHO Collaborating Centers for Chemical Reference Substances in Sweden. The Centre is responsible for obtaining candidate material, ensuring its purity and suitability through analytical tests, and reporting results with recommendations to WHO. In 2005, the Centre distributed a total of 1360 ICRS. Four new ICRS-didanosine, didanosine for system suitability; efavirenz; and nevirapine were adopted by the 41st Expert Committee.

General Guidelines For The Establishment, Maintenance And Distribution Of Chemical Reference Substances:

The requirements of National and regional pharmacopoeia, coupled with the need for greater availability and cost effectiveness, led to the establishment of chemical reference substances external to the WHO Collaborating Centre, and to the development of WHO guidelines to ensure the integrity of national and regional collections. Fist recommended by the committee in 1975, The General Guidelines for Establishment, Maintenance and Distribution of Chemical Reference Substances has undergone several revisions since. The most recent revision is concerned with both primary and secondary chemical reference substances. Part A provides guidance on primary chemical reference substances, materials whose assigned content when used as an assay standard are accepted without requiring comparison to another chemical substance. In response to the Committee’s 2004 recommendations, a new Part B provides more detailed guidance on establishing secondary reference substances, materials whose characteristics are calibrated by comparison with a primary chemical reference substance. This guidance applies primarily to secondary reference substances supplied as regional or national standards. Since producing maintaining and distributing ICRS is costly and time consuming, the guidelines also cover needs assessment (among other protocols). The most important steps addressed are: procuring source material; testing methods and packaging distribution and supply.

GMP for Heating, Ventilation and Air Conditioning (HVAC) Systems:

To ensure that pharmaceuticals are manufactured, packaged and stored in a controlled, uncontaminated environment is a necessary part of the Quality Assurance process. During production and storage, medicines must remain free form impurities, dust and foreign matter. Toxic substances must be contained to prevent there cross contaminating other medicines in adjacent areas or escaping into the outside environment. HVAC systems make this possible by maintaining the proper temperature, humidity and ventilation for medicines and equipment used during manufacture and storage. The guideline advises both manufacturers of solid dosage medicines and inspectors of these facilities on HVAC system design, installation, qualification and maintenance. However, most of the system design principles will also apply to facilities that manufacture medicines in other forms such as liquids, creams and ointments. Since the primary function of pharmaceutical manufacturer’s HVAC system is to prevent contamination and cross contaminations, its design should be part of the facility’s blue print. HVAC design influences the architectural layout of such elements as airlocks, which regulate air flow between rooms of differing classes of cleanliness, and environmentally controlled “CLEAN ROOMS”. HVAC system’s role is protection of pharmaceutical products, personnel and the environment during the manufacturing process.

Model quality Assurance System (MQAS) For Assessment of Procurement Agencies

Low cost pharmaceuticals of assured quality hold a great potential for maximizing the impact of efforts to combat communicable diseases such as HIV/AIDS, Malaria and tuberculosis (TB). Pharmaceutical supply has been a major concern at country and international level, with efforts to accelerate access to medicines highlighting the inadequacies of quality assurance mechanism applied to procurement agencies. While some of these agencies have quality assurance system in place, their extent and quality may vary widely. Without a harmonized system that seeks to ensure procurement of quality medicines for supply to patents, procurement agencies risk sourcing substandard, counterfeit or contaminated medicines. This undermines their credibility and results in product recalls, wasted money and particularly, health risks to patients. In response, the MQAS was designed by expert team, including specialists form UNICEF, UNFPA, WHO and the World Bank, to help these agencies achieve the goal of a quality procurement system. The Model is intended to guide them in developing their own quality assurance systems. It focuses on the four key activities: the prequalification of pharmaceutical products and manufacturers, and the purchase, storage and distribution of pharmaceuticals.

The International Pharmacopoeia

The International pharmacopoeia consists of a collection of quality specifications for pharmaceutical substances (APIs and excipients) and dosage forms, together with supporting general methods of analysis. It is intended to serve as source material for reference or adaptation by any WHO Member state wishing to establish Pharmaceutical requirements. The selection of monographs for inclusion in The International Pharmacopoeia recognizes the needs of specific disease programmes and the essential medicines nominated under these programmes. It is based primarily on those substances included in the current WHO Model List of Essential Medicines.

Equivalence Of Alternative Approaches to Quality Assurance:

The equivalence of alternative approaches to quality assurance should be validated. The guide as a whole does not cover safety aspects for the personnel engaged in manufacture or environmental protection: these are normally governed by national legislation. A new concept of hazard analysis related to the risks in production and personal safety is also newly recommended. The manufacturer should assure the safety of worker and take the necessary measures to prevent pollution of the external environment. International Nonproprietary Names (INNs) for pharmaceutical substances designated by WHO should be used when available, together with other designated names.

Quality Management in Drug Industry:

In drug industry at large, quality management is usually defined as the aspect of management function that determines and implements the “Quality Policy”, i.e. the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are:
- an appropriate infrastructure or “Quality System”, encompassing the organizational structure, procedures, processes and resources;
- systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “QUALITY ASSURANCE”

Within an organization, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier. The concepts of quality assurance, GMP and quality control are interrelated aspects of quality management. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.

Principle: Quality Assurance is a wide ranging concept covering all matters that individually or collectively influence the quality of a product. Quality assurance therefore incorporates GMP and other factors, including product design and development.

The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that:
a. Pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as Good Laboratory Practice (GLP) and Good Clinical Practice (GCP)
b. Production and control operations are clearly specified in a written form and GMP requirements are adopted.
c. Managerial responsibilities are clearly specified
d. Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials.
e. All necessary controls on starting materials, intermediate products, and bulk products and other in process controls, calibrations, and validations are carried out and documented.
f. The finished product is correctly processed and checked, according to the defined procedures.
g. Pharmaceutical products are not sold or supplied before the authorized person have certified that each production batch has been marked authorization and any other regulations relevant to the production, control and release of pharmaceutical products.
h. Satisfactory arrangements exist to ensure, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf life.
i. There is a procedure for self inspection; quality audit that regularly appraises the effectiveness and applicability of the quality assurance system
j. Deviations are reported, investigated and recorded.
k. There is a system for approving changes that may have an impact on product quality.
l. Regular evaluations of the quality of pharmaceutical products should be conducted with the objective to verify the consistency of the process and ensure its continuous improvement.


GMP And Quality Assurance

Good Manufacturing Practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate ot their intended use and as required by the marketing authorization. GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: Cross contamination (In particular of unexpected contaminants) and mix ups (confusion) caused by, for example false labeled container. Under GMP Guidelines
a. All manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications.
b. Qualification and validation performed.
c. All necessary resources are provided: Including:
o Appropriately qualified and trained personnel
o Adequate premises and space
o Suitable equipment and services
o Appropriate material, container and labels
o Approved procedures and instructions
o Suitable storage and transport
o Adequate Personal, laboratories and equipment for in process control.
d. Instruction and procedures are written in clear and unambiguous language, specifically applicable to facilities provided.
e. Operators are trained to carry out procedures correctly.
f. Records are made (manually by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have been taken and quantify and quality of the product are expected; any significant deviations are fully recorded and investigated.
g. Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form
h. The proper storage and distribution of the products minimizes any risk to their quality.
i. A system is available to recall any batch of product from sale or supply
j. Complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.

The manufacture or company must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of concerns in many different departments and at all levels within any organization. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control. It should be fully documented and its effectiveness monitored. All parts of quality assurance system should be adequately staffed with competent personal, and should have suitable and sufficient premises, equipment, and facilities.