Role of regulatory authorities in quality control of

pharmaceuticals

1. Pharmaceutical quality control

The Quality Control department of the PC Pharmaceuticals comprises coordinated

activities for quality control of all the entered and raw materials, thru the manufacturing

process until the production of final product with specified shelf life in appropriate storage

conditions and specification compliant to the strictest European and International standards.

The Quality Control is consisted of several coordinated activities.

1.1 Control of the raw materials, contact and secondary packaging

The control of the active pharmaceutical ingredients, the other compounds and the

contact packaging includes activities for control of their physical and chemical properties and

microbiological characteristics in accordance with the European and internationally

recognized standards. The secondary packaging should provide sufficient and understandable

information to the medical personnel and patients. These activities are performed using

modern validated instruments and techniques such as: infrared spectroscopy with narrow

identification area for each container of incoming raw-material, infrared spectroscopy, total

organic carbon analyzers that analyze the total organic carbon in the water as a medium for

pharmaceutical production, gas chromatography and high performance liquid

chromatography, automatic titration measuring devices, etc.

1.2 Control of the phase production and control of final products

The products are monitored in all the phases of their manufacturing, with all their

specifics by phase, until the final product is delivered which, from the aspect of physical,

chemical and pharmaceutically-technological properties, corresponds to the specifications set

forth by the strictest international regulations.

The activities are performed by employing modern validated instruments such as:

high performance liquid chromatographs, spectrophotometers connected in line to dissolution

equipment and etc.

The analytical methods used for the analysis are continuously upgraded and

modernized and accordingly validated resulting in highest level of safety and confidence of

their performances.

1.3 Microbiological control

This controlling part operates within the new microbiological laboratory constructed

in compliance with the most sophisticated cGMP norms.

In the microbiologically classified areas appropriate equipment has been installed

such as: bio-safety laminar cabinets for analysis performance, incubators, dry sterilizers,

autoclaves, coolers/freezers, microscopes, Vitek II instrument for microorganism's

identification etc. The following activities are carried out by applying coordinated and strictly

determined procedures: control of the products and systems, control of purified water and

other media for pharmaceutical manufacturing, supervision of the premises and equipment

hygiene in the manufacturing facilities as well as all other activities in compliance with the

DPP standards.

As part of the biological tests, the tests for absence of bacterial endotoxins are

performed by modern kinetic turbidimetric methods onto the entry raw materials and the

finished product that are specific for sterile production.

1.4 Stability of the pharmaceutical finished products

Samples from the commercially produced batches are stored in special stability rooms

in conditions that simulate the worst case of outdoor conditions at which the products are

exposed during their lifecycle until the declared expiry date. In determined plans, reanalysis

are performed by which the declared expiry date and the specified storage conditions of the

products are proven to be in accordance to the previously defined specification.

1.5 Validation activities and monitoring

In the frames of the GMP operations, the following analysis are implemented related

to: validation of the analytical methods, validation of the production processes, cleaning

validation of the premises and equipment, validation of the water systems for pharmaceutical

application, compressed air, steam, cleanness of the equipment etc. With previously defined

scheme of critical points in previously defined time frames the routine monitoring of all

defined activities is continuously performed.

The quality inputs of raw materials for manufacturing together with the other

controlled conditions for pharmaceutical production are preconditions for providing of safe

and high quality final product.

1.6 Registration activities

The Quality Control department works on development of the analytical part of the

documentation required for the registration files of the products, which are integral part of the

internationally recognized CTD registration format for pharmaceutical products.

2. Regulatory authorities

A regulatory authority (also regulatory agency, regulatory body or regulator) is

a public authority or government agency responsible for exercising autonomous authority

over some area of human activity in a regulatory or supervisory capacity. An independent

regulatory agency is a regulatory agency that is independent from other branches or arms of

the government.

Regulatory authorities deal in the area of administrative law, regulation

or rulemaking (codifying and enforcing rules and regulations and imposing supervision or

oversight for the benefit of the public at large). The existence of independent regulatory

agencies is justified by the complexity of certain regulatory and supervisory tasks that require

expertise, the need for rapid implementation of public authority in certain sectors, and the

drawbacks of political interference. Some independent regulatory agencies perform

investigations or audits, and some are authorized to fine the relevant parties and order certain

measures.

Regulatory authorities are usually a part of the executive branch of the government, or

they have statutory authority to perform their functions with oversight from the legislative

branch. Their actions are generally open to legal review. Regulatory authorities are

commonly set up to enforce standards and safety, or to oversee use of public goods and

regulate commerce. Examples of regulatory agencies are the Interstate Commerce

Commission and U.S. Food and Drug Administration in the United States, Ofcom in

the United Kingdom, and the TRAI in India.

3. Principles for drug regulatory authorities

Regulation is not the only component of pharmaceutical policy, and sometimes in

resource-limited settings, it is not even the most pressing one. Nonetheless, the existence of a

well-functioning national drug regulatory authority to help ensure medicine quality, safety

and efficacy is the best guarantee that the public is getting the medicines it deserves. A

national regulatory authority needs a clear mission statement including goals and objectives

to direct its work. Goals usually include protecting public health by ensuring the safety,

efficacy, and quality of medicines and their appropriate use. Plainly outlined objectives

provide a measure to evaluate how well the agency is functioning.

Primary pharmaceutical regulation activities should not be compromised by other

non-regulatory tasks with which the national regulatory authority may be charged. If the

authority responsible for pharmaceutical regulation has non-regulatory functions, such as

manufacturing, procurement, or service delivery, conflicts of interest may occur regarding

mandates and resource allocation.

When a country is ready to introduce pharmaceutical regulation, work by WHO

(1990) provides useful guidance for authorities with limited human, financial, scientific, and

technological resources. To be effective, a small drug regulatory authority needs to operate

within the national pharmaceutical laws and policies that have been established and must

relate to other interested bodies, including organizations responsible for pharmaceutical

procurement in public sector and the national formulary committee. As mentioned,

effectively enforcing pharmaceutical legislation requires national regulatory authorities and

other government enforcement agencies, such as customs, police, and prosecutor, to work

together. National regulatory agencies should also seek the cooperation of health

professionals, pharmaceutical and consumer associations, and other interested parties through

stakeholder workshops, meetings addressing specific issues, or other venues open to the

public.

A drug regulatory authority’s objectives can be accomplished effectively only if a

mandatory system of licensing products, manufacture, importing agents, and distributors is in

place. A small authority has limited capacity to undertake these tasks. For imported

pharmaceutical substances, a small authority is dependent on information generated in the

exporting country.

The World Health Organization (WHO) certification scheme on the quality of

pharmaceutical products moving in international commerce (WHO 2000) was designed to

provide this information, although recommendations have been made on how to update the

scheme (WHO 2008). This scheme must be supplemented by direct contacts with

international agencies and other regulatory agencies to obtain necessary information.

However, the certification scheme is only as good as the certifying authority. WHO’s

prequalification program provides information on approved sources for products related to

HIV/AIDS, malaria, tuberculosis, and reproductive health.

Many national regulatory authorities do not make publicly available their regulatory

policies, administrative procedures, guidelines, and criteria for decisions. Lack of

transparency means that communication is probably lacking on medicine regulation between

national regulatory authorities and their stakeholders.

Moreover, transparency is required to make the agency accountable for its actions and

to limit the influence of political pressures and personal favors in the decision-making

process. Transparency will also contribute to the credibility and authority of communications

between the agency and those affected by its actions: manufacturers, importers, distributors,

health professionals, and consumers. An assessment tool is available to measure transparency

in the pharmaceutical sectors (WHO 2009a) and a report describes the assessment of four

countries’ pharmaceutical registration, selection and procurement systems: Malaysia,

Phillipines, and Thailand.

To increase the amount of information and communication, WHO is helping drug

regulatory authorities develop websites with information on:

Lists of approved medicines

National pharmaceutical regulations

Methods to ensure safe, efficacious, and rational use of specific medicines

List of approved companies and their authorized activities

Details of persons and institution with responsibility for pharmaceutical regulation

4. International Conference on Harmonisation of Technical Requirements

for Registration of Pharmaceuticals for Human Use (ICH)

The International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the

regulatory authorities of Europe, Japan and the United States and experts from

the pharmaceutical industry in the three regions to discuss scientific and technical aspects of

pharmaceutical product registration.

The purpose of ICH is to reduce or obviate the need to duplicate the testing carried

out during the research and development of new medicines by recommending ways to

achieve greater harmonisation in the interpretation and application of technical guidelines and

requirements for product registration. Harmonisation would lead to a more economical use of

human, animal and material resources, and the elimination of unnecessary delay in the global

development and availability of new medicines while maintaining safeguards on quality,

safety, and efficacy, and regulatory obligations to protect public health.

ICH guidelines have been adopted as law in several countries, but are only used as

guidance for the U.S. Food and Drug Administration.

Since its inception in 1990, ICH has gradually evolved, to respond to the increasingly

global face of drug development, so that the benefits of international harmonisation for better

global health can be realised worldwide. ICH's mission is to achieve greater harmonisation to

ensure that safe, effective, and high quality medicines are developed and registered in the

most resource-efficient manner. 

5. Role of regulatory authorities

To ensure that it does fill its role, a regulatory authorities uses mechanisms such as the

following

Transparency of information and decision-making

Procedures of consultation and participation

Requirement that administrators give reasons explaining their actions

Requirement that administrators follow principles that promote non-arbitrary and

responsive decisions.

Arrangements for review of administrative decisions by courts or other bodies

6. Regulation of therapeutic goods

The regulation of therapeutic goods, that is drugs and therapeutic devices, varies

by jurisdiction. In some countries, such as the United States, they are regulated at the national

level by a single agency. In other jurisdictions they are regulated at the statelevel, or at both

state and national levels by various bodies, as is the case in Australia.

The role of therapeutic goods regulation is designed mainly to protect the health and

safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of

the therapeutic goods which are covered under the scope of the regulation. In most

jurisdictions, therapeutic goods must be registered before they are allowed to be marketed.

There is usually some degree of restriction of the availability of certain therapeutic goods

depending on their risk to consumers.

7. Pharmaceutical quality system

The term “pharmaceutical quality system” refers to the ICH Q10 model. ICH Q10

describes one comprehensive model for an effective pharmaceutical quality system that is

based on International Standards Organisation (ISO) quality concepts, includes applicable

Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical

Development” and ICH Q9 “Quality Risk Management”.

ICH Q10 is a model for a pharmaceutical quality system that can be implemented

throughout the different stages of a product lifecycle. Much of the content of ICH Q10

applicable to manufacturing sites is currently specified by regional GMP requirements. ICH

Q10 is not intended to create any new expectations beyond current regulatory requirements.

Consequently, the content of ICH Q10 that is additional to current regional GMP

requirements is optional.

ICH Q10 demonstrates industry and regulatory authorities’ support of an effective

pharmaceutical quality system to enhance the quality and availability of medicines around the

world in the interest of public health. Implementation of ICH Q10 throughout the product

lifecycle should facilitate innovation and continual improvement and strengthen the link

between pharmaceutical development and manufacturing activities.

7.1 Scope of ICH

This guideline applies to the systems supporting the development and manufacture of

pharmaceutical drug substances (i.e., API) and drug products, including biotechnology and

biological products, throughout the product lifecycle.

The elements of ICH Q10 should be applied in a manner that is appropriate and

proportionate to each of the product lifecycle stages, recognising the differences among, and

the different goals of each stage.

For the purposes of this guideline, the product lifecycle includes the following

technical activities for new and existing products:

Pharmaceutical Development:

o Drug substance development

o Formulation development (including container/closure system)

o Manufacture of investigational products

o Delivery system development

o Manufacturing process development and scale-up

o Analytical method development

Technology Transfer:

o New product transfers during development through manufacturing

o Transfers within or between manufacturing and testing sites for marketed

products

Commercial Manufacturing:

o Acquisition and control of materials

o Provision of facilities, utilities, and equipment

o Production (including packaging and labelling)

o Quality control and assurance

o Release

o Storage

o Distribution (excluding wholesaler activities)

Product Discontinuation:

o Retention of documentation

o Sample retention

o Continued product assessment and reporting

7.2 Relationship of ICH Q10 to Regulatory Approaches

Regulatory approaches for a specific product or manufacturing facility should be

commensurate with the level of product and process understanding, the results of quality risk

management, and the effectiveness of the pharmaceutical quality system. When implemented,

the effectiveness of the pharmaceutical quality system can normally be evaluated during a

regulatory inspection at the manufacturing site. Potential opportunities to enhance science

and risk based regulatory approaches are identified. Regulatory processes will be determined

by region.

7.3 Objectives of ICH Q10

Implementation of the Q10 model should result in achievement of three main

objectives which complement or enhance regional GMP requirements.

a) Achieve Product Realisation

- To establish, implement and maintain a system that allows the delivery of

products with the quality attributes appropriate to meet the needs of patients,

health care professionals, regulatory authorities (including compliance with

approved regulatory filings) and other internal and external customers.

b) Establish and Maintain a State of Control

- To develop and use effective monitoring and control systems for process

performance and product quality, thereby providing assurance of continued

suitability and capability of processes. Quality risk management can be useful in

identifying the monitoring and control systems.

c) Facilitate Continual Improvement

- To identify and implement appropriate product quality improvements, process

improvements, variability reduction, innovations and pharmaceutical quality

system enhancements, thereby increasing the ability to fulfil quality needs

consistently. Quality risk management can be useful for identifying and

prioritising areas for continual improvement.

8. Role of pharmaceutical legislation and regulation

The role of pharmaceuticals has become more prominent on international agendas as

health indicators have been increasingly linked with a country’s successful development. In

addition, the legal and economic issues that surround pharmaceuticals have become more

complex and politicized because of the increase in global trade.

Because so many parties are involved with medicines, the laws need to clearly state

the roles, responsibilities, and rights of each, ranging from practitioners, auxiliaries, nurses,

and pharmacists to importers, manufacturers, and distributors. Countries approach prescribing

and dispensing differently, depending on their circumstances; for example, in Canada, a

physician must be the medicine prescriber, but in areas where physicians are scarce, legal

authority may be granted to nurses or other health practitioners to prescribe essential

medicines. The legislation should establish the qualifications required for those handling

medicines, or it must state who has the authority to set these standards by passing appropriate

regulations (for example, a government minister).

8.1 Licensing, inspection, and quality control

The law should create mechanism to ensure that relevant parties are licensed and

inspected so the community can have confidence in them. Doctors and nurses may be

covered by other laws, but the medicine law needs to ensure that people who import,

distribute, and sell medicines are properly qualified, approved, registered, and inspected.

Pharmaceuticals themselves require a special form of inspection. An inspector visiting

a pharmacy or warehouse may have reason to suspect that medicines are not of sufficient

quality or in good condition: they may be damp, dirty, or disintegrating. More often, samples

need to be obtained for testing in the quality-control laboratory, an essential part of the

inspection system.

Some countries have their own quality-control laboratories, either specifically for

medicines or shared with other commodities (such as foods). A number of countries use

regional laboratories, such as the ones serving sub-Saharan Africa or the Caribbean.

Whatever the structure, the pharmaceutical law needs to designate a quality-control

laboratory that has the capacity and equipment to do the job.

Countries that have pharmaceutical manufacturing operations should enforce good

manufacturing practices (GMP), which is a system to ensure that products are consistently

produced and controlled according to quality standards. GMP covers all aspects of production

from the starting materials, premises, equipment, and quality testing to the training and

personal hygiene of staff. WHO has established detailed guidelines for good manufacturing

practice, and many countries have formulated their own requirements based on WHO’s GMP.

Other regions, such as the Association of Southeast Asian Nations and the European Union,

have harmonized their GMP requirements.

Although important, GMP monitoring sometimes receives more resources than the

inspection of distribution channels; however, the consumer’s interest is not served by

manufacturing a product under GMP but then storing and distributing it under adverse

conditions. Inspection of distribution channels, including the importation of pharmaceuticals,

should also be emphasized, particularly in countries where the distribution system has several

intermediate levels or the climate is unfavorable. WHO has produced guidelines relating to

good storage practices for pharmaceuticals (WHO 2003a).

8.2 Pharmacovigilance

The law should also provide a basis for a pharmacovigilance (that is, post-marketing

surveillance) system to report problems with adverse reactions and product quality.

Pharmacovigilance is defined by WHO (2002a) as “the science and activities relating to the

detection, assessment, understanding and prevention of adverse effects or any other drug-

related problems”.

Pharmacovigilance is an overacting concept that encompassed any system used to

monitor medicine safety, use, and efficacy. For example, adverse drug reaction monitoring as

part of a product’s post-marketing surveillance contributes to the assessment of benefit,

effectiveness, and risk of medicines. A pharmacovigilance system is difficult if not possible

to implement in an unregulated market that allow the importation and sale of pharmaceuticals

which provides a clearinghouse for the millions of adverse drug reaction reports reveived

from almost 100 countries. International pharmacovigilance activities have had a notable

effect on international drug regulation.

8.3 Advertising and promotion

Although many countries have rules to ensure that advertising is not misleading, thses

rules are generally not sufficient to cover pharmaceuticals. With consumer products, a certain

degree of exaggeration is often tolerated as the normal practice of the marketplace. But for

medicines that have the capacity to kill or cure, and with claims that people cannot easily

verify, it is important that advertising to health professionals and to consumers be objective

and reliable; misleading and extravagant pharmaceutical advertising claims may pose

significant risks to the public.

For these reasons, most laws on pharmaceuticals now include a clause empowering

regulation on advertising. In many countries, it is illegal to advertise to consumers medicines

intended to be prescribed by health professionals. However, direct promotion of

pharmaceutical products through the internet is practically impossible to control; therefore,

the national regulatory agency should educate consumers on identifying reliable sources of

information, preferably in collaboration with national consumer and professional

organizations. All advertising and labeling must be consistent with the information verified

when the pharmaceutical product was registered or approved for marketing, with

modifications required by the regulatory authority on the basis of post-marketing experience.

8.4 Sanctions

Because constant vigilance is needed if the public is to be protected, pharmaceutical

laws must be properly enforced with appropriate penalties for violators. There is no use

establishing that medicine quality is poor, a warehouse is rat infested or damp upon

inspection, or an advertisement is untruthful unless something is done about it. The drug

regulatory agency must use its authority to impose appropriate penalties when necessary:

sanctions may be penal (fines, imprisonment, or both) or simply corrective (banning the drug,

closing down the warehouse). Sometimes a party has contravened the law so seriously that

the appropriate sanction is determined to be loss of license to prescribe, manufacture, import,

or distribute. On occasion, all of the penalties may be imposed.

To be effective, the drug regulatory authority must be able to apply sanctions on a

timely basis, so it must have either the legal staff to ensure compliance or the necessary links

with the relevant government department charged with enforcement. Therefore, the law

governing pharmaceutical products must give legal authority to the appropriate personnel to

carry out any necessary enforcement activities.

In addition, because the pharmaceutical sector is vulnerable to corruption, a country

should not only include an anticorruption mechanism in its regulatory framework, but also

have sanctions in place for bribery, fraud, collusion, and other dishonest acts (WHO/PSM

2006). Many countries have specific laws that address corruption in the public sector or

provisions in their procurement regulations to ensure transparency and provide sanctions

against, for example, bribery.

9. Evaluating the effectiveness of pharmaceutical legislation

Evaluating the effectiveness of pharmaceutical legislation and accompanying

regulations is not always easy. The process of evaluation depends on the types of

performance indicators and criteria used and on the availability of adequate data.

The most important factor in the effectiveness of pharmaceutical laws and regulations

is the extent to which the legislative framework is in tune with national policy and the

existing situation in the pharmaceutical sector. Changes in policy need to be reflected in the

legislation and in its implementation. Measuring the effectiveness of a law on

pharmaceuticals is easier for certain elements than for others. For instance, the registration

process can be evaluated in relation to quantitative targets and time schedules to see whether

the agency is on schedule.

The degree of non-compliance with a law or regulation may suggest not only the need

to take action against those responsible but also the desirability of identifying the causes of

non-compliance: it may be related to technical defects in the law or in its wording, or to

operational problems of implementation, such as lack of transparency or poor

communication, which can be resolved. Enforcement personnel should periodically report on

their perception of how the law functions and the types of problems encountered to facilitate

any necessary revisions. Many legislative and regulatory provisions can be improved and

updated when the legislation is sufficiently flexible to allow for modifications by the

regulatory agency.

Responsibility for evaluating the effectiveness of a drug law often falls on the

regulatory authority established by law for policy making, implementation, or both. The level

of accountability and transparency under which the drug regulatory authority operates can be

evaluated by examining reporting requirements, external reviews of performance, process

involved with lodging complaints, and appeals procedures. Periodic self-evaluation to

identify weaknesses in policy making and implementation activities is important. The body

must devise its own systems to judge whether it receives sufficient feedback and whether its

operational effectiveness can be improved.

10. Conclusion

Recommendations and guidelines provide an essential foundation for the development

and maintenance of quality assurance of pharmaceutical products. But it is personnel who are

crucial to quality assurance at all levels of pharmaceutical manufacture, regulation and

distribution.

Pharmacists have an important contribution to make in public health and particularly

in the field of medicines. WHO meetings on the role of the pharmacist in the health care

system were held in New Delhi in 1988 and in Tokyo in 1993, and the World Health

Assembly, in resolution WHA47.12, has stressed the key role pharmacists can play in the

rational use and quality assurance of medicines.

By virtue of their training, pharmacists can play a part in drug regulation and control,

particularly in the evaluation of pharmaceutical formulations at the time of product

registration, and in the licensing and inspection of pharmaceutical manufacturing plants and

distribution channels. In addition to their work in central medical stores, hospitals,

pharmacies and other drug outlets, trained pharmacists may also contribute to quality

assurance by assisting in pharmaceutical manufacture, in drug procurement and in

distribution.

While quality assurance is founded on regulations and standards, it is the people who

enforce the regulations or work to comply with the standards who make the difference

between quality assurance and lack of it. The assurance of quality, safety and efficacy of

medicines is a continuing concern of WHO. This compilation of material is intended to assist

all involved in the manufacture, regulation and distribution of pharmaceuticals to achieve

these aims more effectively.

11. References

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