The role of QA in the current regulatory scenario is ever increasing and encompasses the activities performed by different departments in an organization. This article traces in brief a few incidents which triggered stringent national and international drug manufacturing regulation. As the regulations rightly mentions, "Quality is the responsibility of all the persons involved in the manufacturing" and not just of the QA department. This article describes the role of the QA department throughout the life cycle of the drug including during the drug development stage where this activity is performed by Development QA team. The article further describes in depth the role of QA during commercial manufacturing of products and concludes how a strong, active and responsive QA is an asset to any organization.

There are a number of Industries which are important for the consumer. The food, cosmetic and pharmaceutical industries are of primary importance since they are directly used by the consumer for internal consumption or for local application. The quality, efficacy and safety attributes of these products must hence be ensured so that the consumer health is not compromised.

With the improvements in medication and healthcare the quality of life and the life expectancy of the people have increased over the years. Quoting the Indian Health Report -September 2010 published by the Government of India Ministry of Health and Family Welfare:

"Life expectancy in India has more than doubled in the last sixty years. It increased from around 30 years at the time of independence to over 63.5 years in 2002-06".

As per the WHO Global Health Observatory report:

Life expectancy at birth reflects the overall mortality level of a population. It summarizes the mortality pattern that prevails across all age groups in a given year - children and adolescents, adults and the elderly. In 2011, life expectancy at birth globally was 70 years.

The consumption of medications and health supplements is increasing worldwide every year. Worldwide sales of medicines reached 1.08 trillion USD in 2011 (an increase of 7.8%over the previous year) and are expected to reach 1.5 trillion USD by 2020 as per the Price Water Cooper report on the pharma industry.

To cope with this increasing demand for pharmaceutical products the number of companies producing the same has increased. In 2002, over 20,000 registered drug manufacturers in India sold $9 billion worth of formulations and bulk drugs. 85% of these formulations were sold in India while over 60% of the bulk drugs were exported, mostly to the United States and EU. Most of the players in the market are small-to-medium enterprises; 250 of the largest companies control 70% of the Indian market.

Along with an increase in number, over the last 10 years there has been a number of mergers and acquisitions of Indian and MNC pharmaceutical companies for leveraging their strengths resulting in increasing the profitability and effectiveness of the pharmaceutical manufacturing. Today there are a number of Indian companies in close tie ups with global MNC pharma companies for developing, producing and marketing pharmaceutical products.

In order to ensure quality, safety and efficacy of products, every country has their regulatory agencies which regularly review and inspect the company's manufacturing sites where these drugs are manufactured. Additionally there are internationally recognized regulatory bodies whose approval is required before the drug substances and drug products can be exported and sold in the respective countries. To name a few: US FDA in USA, MHRA in UK, Health Canada in Canada, TGA in Australia, MCC in South Africa, ANVISA in Brazil, COFEPRIS in Mexico, the WHO etc.

The origin and need for national and international drug manufacturing regulation and the subsequent tightening of the regulations find roots in a number of incidents resulting in fatal side effects or deformities. To name two:

In 1937, the Massengill Company used the solvent diethylene glycol, which is also used as antifreeze to make a palatable liquid version of its then new antibiotic drug sulfanilamide. As a result of which Elixir Sulfanilamide killed 107 people, mostly children, before it was quickly recalled. After this tragedy the Food, Drug, and Cosmetic Act of 1938 was enacted which required that drugs had to be proven safe prior to marketing.

Thalidomide was a drug used for treatment of morning sickness. However when pregnant women took this drug, it led to babies born with deformities. To deal with such situations the PDA amended its regulation through the Kefauver-Harris Amendments of 1962, to ensure that the efficacy of the drug had to now be proven prior to marketing.

In any pharmaceutical company there are a number of departments which are involved in the development, manufacturing and marketing of the drug product and these include the R&D, purchase, production, stores, engineering, QC, QA and marketing. The role and responsibilities are defined for each department. Quality control department is responsible for testing the raw materials, in- process samples, intermediates, APIs finished products and the stability samples. Traditionally the quality of a product was determined only by the testing of the product and determining that it complied with the established specification. However the regulatory agency requirement today is that quality is not determined only by end product testing but quality is to built up into the product. This entails that at each step quality is to be ensured right from drug development to the finished product manufacturing and sale.

As the ICH Q7 rightly says:
"Quality is the responsibility of all the persons involved in the manufacturing".

Pharmaceutical regulations talks about the establishment of a quality unit which is independent of production. The responsibilities of the quality unit include both the responsibilities of quality control - QC and quality assurance -QA departments. The top level management in any organization has the responsibility of actively participating in the quality management. It is a well known belief that quality initiatives are successful only when it is driven from top management to the lower levels of management.

The QA department plays an important role throughout the life cycle of the drug substance and drug product and is mentioned as given below:

A. Drug development.
The R&D department is responsible for the development of a manufacturing process by which the intended product will be manufactured. In case of API the first step the R&D scientists would do is a literature survey of existing processes for manufacturing the product. Based upon the R&D experiments a process would be developed which is unique and not infringing any existing patent. Along with R&D the API analytical development develops the test procedures for the analysis of raw materials, intermediates, in process tests and API's. In the R&D the QA involved is often referred to as the Development QA-DQA.

The role of DQA in case of API R&D development is to:
1.     To ensure that the raw materials used in the manufacturing are qualified and that all data including the vendor qualification, route of synthesis, declarations a re available.
2.     To ensure that all R&D and analytical development data is recorded by the R&D scientists in laboratory notebooks and is reviewed for accuracy and traceability. This data should be recorded as per the requirements of GMP and should be securely stored/archived for future reference.
3.    To ensure that the critical process parameters in an API manufacturing process are identified, required testing methods are validated and the R&D batches are initiated for stability.
4.    To ensure that a system is in place for document control and that procedures are in place for performing the activities, operating and calibrating the equipment and training the personnel.

All the above data concerning drug substance or drug product will be compiled into a development report which will be approved by the DQA. This development report will be used to transfer the manufacturing process from small scale batches in the R&D to bigger batch sizes in the manufacturing facility.

In addition, in case of Formulation R&D the DQA reviews the different formulations developed by R&D and the rationale of the R&D for the selected formulation.

In the case of formulation batches used for clinical trials the clinical QA team is involved in all areas concerning the trials-selection of volunteers for the trials, review of the analytical testing data and submission of the clinical studies.

B. Drug manufacturing.
Plant QA plays a pivotal role at the manufacturing facility to ensure that the Quality is built up in the plant in letter and spirit. It ensures that a rugged Quality system is in place. The role of QA is evidenced throughout the life cycle of the product. Some of the important roles performed by Plant QA are:
1.     All the key documents including the Quality Policy and Objectives, Quality Manual and Validation Master Plan are prepared and approved by the QA department.
    The Quality Policy is prepared in consultation with the top management and will be in line with vision of the organization
    The Quality Objectives and the departmental objectives achievement are monitored periodically by the Management Representative who in many organizations is theQA Head.
2.     The Validation Master Plan establishes the overall validation philosophy of the organization. QA approves this VMP and monitors the implementation to ensure that all validation activities are completed as per the schedule.
3.    QA is responsible to ensure that the process of manufacturing the API or the formulation is provided by the R&D through a technology transfer. Analytical method transfer and method validation is also to be ensured from the R&D analytical development teams to the plant QC team.
4.    QA ensures that all changes impacting the product and the established systems at a manufacturing facility are documented and reviewed to analyze the impact of this change. The proposed changes are discussed by a change control committee consisting of the different department heads. Additionally the consent of the regulatory department and of the customer may be taken depending on the nature of the change.
Based on the comments of the change control committee, QA will recommend to the activities/studies which need to be performed.

For example:
a.    In case of a change of drying equipment used in API stage manufacturing from a simple tray drier to a vacuum tray drier, QA would typically recommend that the vacuum tray drier be qualified and the drying validation of the API be repeated.
b. In case of increase in batch size, QA would typically recommend that the process be revalidated and batches be initiated for stability.
c.     In case of changes performed in the existing manufacturing process, QA ensures that that there is sufficient R&D data to justify the change. Based on the nature of the change, process validation will be performed and stability initiated as applicable.
5.    In order to ensure a quality product is consistently manufactured it is important that the equipment is used for the manufacturing and the testing are qualified .QA ensures that all equipments and instruments are qualified, calibrated before use and qualification and calibration documents are in place for the same. Qualification is also required for critical utilities like HVAC's, water system, nitrogen gas and compressed gas generation and distribution systems.
6.     Calibration of equipment and instruments ensures the reliability of the equipment and the data obtained from it. QA approves the calibration calendar for both QC and engineering departments and monitor that these calibrations are completed within the target dates. Out of calibration instruments cannot be used for testing and such equipments should be prominently labeled to prevent inadvertent use by the QC analysts or production chemists.
7.     To ensure the consistent performance of equipments it is important to ensure that the equipments and instruments are periodically maintained as per an established planned preventive maintenance programme which is approved by QA. The checklists for performing these tasks are usually part of SOP's approved by QA. All equipment and instrument breakdowns must be recorded along with the actions taken in the equipment history cards. Equipment history cards provide a wealth of information during any failure investigation and today many organizations regularly perform breakdown analysis which helps to predict and prevent the breakdowns by increasing the intervals of preventive maintenance as required. These also help in maintaining the reorder levels of spares. In case product manufacturing is affected by the breakdown then it is routed through a deviation which is approved by QA and a CAPA plan needs to be initiated and executed before closure of this deviation.
8.    QA ensures that the specifications and test procedures are in place for all raw materials, packing materials intermediates, in process testing, API's and stability testing
9.     Recruitment and training; It is essential that the personnel suiting the job role are selected and are trained for the purpose. Although training may be performed by the HR department, QA reviews training records to ensure that the training calendar is followed. It is essential that all new recruits undergo an induction training and on the job training before performing the routine activities. It is also essential that in QC the analysts are validated.
10.    During the manufacturing process or during the operations, deviations may occur from the established procedures. QA ensures that all such deviations are logged, investigated to identify the root cause for the deviation so as to take measures to prevent recurrence of the same. For this an investigation team may be formed consisting of members from different departments. In some cases there may be a need to deviate from the established process and this is termed as a planned deviation. In some organizations this is termed as a temporary change. Such deviations are usually for a fixed period or fixed number of batches. For example use of reduced batch size due to limited availability of key starting material due to campaign closing.
11.    After the dispatch of the batch to the market the customer may send a complaint if the product does not meet the agreed quality attributes or if received in a damaged condition or with foreign matter. It is the responsibility of QA to immediately log the complaint and acknowledge the same to the customer. Investigation into the cause of the complaint will be initiated under the supervision of QA and may also be extended to batches preceding or succeeding the affected batch. QC testing of the control sample and complaint sample (if available) and a detailed review of the manufacturing, environmental, cleaning, training records may help in the investigation and establishing a CAPA plan to prevent recurrence. A detailed report on the investigation and the CAPA plan is then provided to the customer.

Sometimes a complaint concerning an API batch may require a batch to be returned from the customer. QA ensures that this market return is documented and investigated. The fate of a returned batch depends on the nature of the complaint. It may be reprocessed if a procedure is available for the same from the R&D. If it cannot be salvaged it is destroyed and the destruction is documented.

In case of pharmaceutical products if the market complaint is due to failure of a product ' to meet the specification, the product will be returned and destroyed as there is no reprocessing for finished products. If the defect was identified after distribution in the market QA is responsible to consult with the top management and initiate a product recall from all levels-distributor, chemist and patient. Such recalls have to be intimated to the concerned regulatory authorities. Post marketing experiences like adverse drug reactions may also necessitate the need of a product recall and informing regulatory authorities.
12.    Quality Assurance department trains and leads the team involved in the periodical performing of the internal audits of all the departments. These audits help to identify gaps in the existing system, deviations and non compliance so that remedial action can be taken in a timely manner.
13.    It is the QA department which interfaces with auditors during regulatory and customer inspections .QA department is hence responsible to inform top management about product failures, inspection observations, major quality complaints, recalls etc.
14.    Prior to release of any batch of intermediate, API or finished product QA ensures that the related batch manufacturing records and QC testing data is reviewed and approved. In cases of release of pharmaceutical products In Europe this activity of batch release is performed by technically competent Quality Person (QP).In India the manufacturing chemists and testing personnel should be approved staff by local PDA.
15.    If the result of testing of any batch of raw material, packaging material ,intermediate or stability sample reveals that it does not meet the established and approved specification then it is the responsibility of QC to inform QA to initiate an Out of specification investigation. The preliminary investigation is performed at the QC lab to confirm that the testing was performed exactly as per the procedure and that there was no analyst error, equipment malfunction etc as a result of which the OOS occurred. Once the OOS is confirmed a cross functional team under QA leadership conducts an in depth investigation into the cause of the OOS. This would include the detailed review of the manufacturing procedures followed for the OOS batch, raw materials used, in process testing results, yields, training status of personnel involved in manufacturing and testing. Some of the techniques used include the usage of the Ishikawa diagrams (also called fishbone diagrams, cause-and-effect diagrams) are causal diagrams created by Kaoru Ishikawa (1968) that show the causes of a specific event.

Causes are usually grouped into major categories to identify these sources of variation. The categories typically include:
a.     People: All the personnel involved with the manufacturing process of the affected batch.
b.     Methods: How the process is performed.
c.      Machines: Machinery, equipment, utilities tools, etc. required to complete the process
d.     Materials: Raw materials used to produce the final product
e.      Measurements: Data generated from the process that are used to evaluate its quality
f.      Environment: The environmental conditions such as location, time, temperature etc in which the process operates
16.    QA is responsible to ensure that periodic trending of product manufacturing and testing data are prepared and reviewed. This will include the trending of the critical process parameters and quality data of key raw materials and critical materials as well as trend of testing results of intermediates, APIs and finished products. A number of statistical software are available today for this purpose and also helps to identify Out of trend results which must be recorded by QC and investigated by a team led by QA. Environmental monitoring data including the microbial monitoring of clean room areas and water for pharmaceutical use must also be trended. This ensures that emerging trends are identified in a timely manner and appropriate corrective and preventive actions are taken. These trending reports are then collated as Annual product quality reports (APQR). The APQR also includes the summary details of the changes initiated for the product, deviations, OOS, Out of trend, customer complaints, details of batches initiated for stability as well as review of the existing stability data, control sample reviews.
17.    It may sometimes be necessary to perform certain tests or calibrations at external testing a laboratories and calibration agencies since in house capabilities are not available for the same. In such cases these laboratories need to be qualified by QA and audited to ensure suitability before use. A quality agreement approved by the Quality Heads of both organizations must be in place and must clearly mention the responsibility of the contract giver and contract acceptor. These agreements must be periodically reviewed.
18.    In some cases an organization may decide to manufacture part of the process or an intermediate or the complete product at another manufacturing site. QA is responsible to prepare the Quality and Technical agreement and to review the manufacturing activities at the site.
Hence it is evident that the role of QA straddles many areas and has the overall important responsibility for maintaining Quality at a manufacturing site. A strong, active and responsive QA is an asset to any organization. These multifaceted roles can be achieved only by the co-operation of all departments who must work as a team along with a strong commitment of the top management.