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News and Events:

Function owners subject to public law

Here you will find answers to the following questions:

  • What prerequisites have to be met by the function owners subject to public law?
  • What tasks/responsibilities do they have?

Function owners subject to public law include:

  • Qualified Person (chapter 1 Qualified Person (QP)))
  • Head of Production (chapter 2 Head of Production)
  • Head of Quality Control (chapter 3 Head of Quality Control)
  • Qualified Person in accordance with Article 103 of Directive 2001/83/EC (chapter 4 Qualified Person in Accordance with Article 103 of Guideline 2001/83/EC)
  • Scientific service in charge of information (chapter 5 Scientific Service in Charge of Information)
  • Medical sales representatives (chapter 6 Medical sales representatives)

1 Qualified Person (QP)

1.1 Requirements of the Qualified Person in accordance with European law

For Europe, the qualification requirements for the Qualified Person are defined in Article 49 of Directive 2001/83/EC (figure 2.D-1).

Figure 2.D-1 EU qualification requirements for the Qualified Person

Qualification requirements in accordance with Article 49 of Directive 2001/83/EC

The Qualified Person must hold a degree, certificate or other form of evidence that he or she has completed an academic course of training or its equivalent in one of the member states in question, lasting at least four years and including theoretical and practical instruction in one of the following scientific subject areas: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology.

A minimum course duration of three and a half years may, however, be permissible if it is followed by at least one years' theoretical and practical training that includes a placement in a pharmacy lasting at least six months, involving contact with the public and culminating in a university-level exam.

If a member state offers two academic courses or training courses that it acknowledges as equal to academic courses, of which one lasts four years and the other three, it is to be assumed that the degree, certificate or other evidence of completion of the academic or equivalent training lasting three years meets the requirements for duration specified in subclause 2, providing that the degrees, certificates, or other proof of course completion are recognised as equal by this state.

The training course contains theoretical and practical instruction in the following basic subject areas, as a minimum:

  • Experimental physics
  • General and inorganic chemistry
  • Organic chemistry
  • Analytical chemistry
  • Pharmaceutical chemistry, including drug product analysis
  • General and applied (medical) biochemistry
  • Physiology
  • Microbiology
  • Pharmacology
  • Pharmaceutical technology
  • Toxicology
  • Pharmaceutical biology (study of the composition and effects of natural active substances of plant-based or animal origin)

Instruction in these subjects must be balanced in such a way that it enables the student in question to fill his or her obligations as stipulated in Article 51 of this Directive.

If certain degrees, certificates or other evidence of completion of a training course in accordance with subclause 1 do not meet the criteria stated in this clause, the responsible offices in the member state must be satisfied that the individual in question has demonstrated sufficient knowledge in the relevant subject areas.

The Qualified Person must have been employed for at least two years in one or more organisations with manufacturing authorisation, working in the area of qualitative analysis of drug products and quantitative analysis of their active ingredients, as well as the trials and tests that are necessary to establish the quality of the drug product. The amount of practical experience required may be reduced by one year if the individual has completed an academic training course lasting at least five years, and by one and a half years if the course lasted a minimum of six years.

In order to obtain a manufacturing authorisation for approving pharmaceutical products for placement on the market, a Head of Production and Head of Quality Control must be appointed in addition to the Qualified Person, and suitable premises and facilities must be demonstrated. The Head of Production and the Head of Quality Control must be independent from one another (see EU-GMP Guideline, chapter 2.3, see chapter C EU GMP Guide). The assessment of the Head of Manufacturing or Quality Control's specialist qualifications and practical experience carried out by the authorities responsible as part of the manufacturing or import licence issuing process will therefore be performed on a case-by-case basis.

1.2 Area of responsibility of the Qualified Person in accordance with European Law

For Europe, the duties of the Qualified Person are defined in Article 51 of Directive 2001/83/EC (see figure 2.D-2). Correspondingly, they are also described in the EU-GMP Guideline, Chapter 2, No. 4.

Figure 2.D-2 Duties of the Qualified Person in accordance with Article 51 of Directive 2001/83/EC

Duties of the Qualified Person in Accordance with
Article 51 of Directive2001/83/EC

1. Ensuring that, for drug products manufactured in the member state in question, each batch of drug product is manufactured and tested in accordance with the laws applicable in this member state and the requirements upon which approval for placing on the market is based.

2. Ensuring that, in the case of drug products imported from third countries irrespective of whether they were manufactured in the EC, every batch of drug product has undergone a complete qualitative analysis, quantitative analysis of at least all active ingredients and any other trials and tests that are necessary to guarantee the quality of the drug product in accordance with the requirements upon which approval for placing on the market is based.

3. Batches of drug products checked in this manner in a member state are exempt from the checks stipulated upon import to another member state if inspection reports signed by the Qualified Person are enclosed.

4. If, in the case of drug products that have been imported from a third country, appropriate agreements have been made between the EC and the country of export that guarantee that the manufacturer of the drug product has followed instructions during manufacturing that, as a minimum, correspond to the instructions specified by the EC, and that the checks described in 2. have been carried out in the country of export, the Qualified Person is no longer required to carry out these tasks.

5. In all cases, but in particular as soon as the drug products are put into circulation, the Qualified Person must certify in a record or equivalent document intended for the purpose that each production batch complies with the provisions of this article; individual operations must be entered consecutively in the designated record or equivalent document; these records or documents must be available to the agent or responsible authorities within a time period designated by the law of the member state in question, but not less than five years.

Release for placement on the market

Before the Qualified Person can issue a release for placement on the market, he or she must either ascertain personally or receive confirmation from other sufficiently qualified and suitable persons that the manufacturer is in a position to manufacture and perform tests in conformity with good manufacturing practice and in accordance with manufacturing and testing procedure. Auditing of third parties is an important routine task to be performed by the Qualified Person (see EU-GMP Guideline, chapter C.6.16 Annex 16 Final Version: Certification by a Qualified Person and Batch Release). Other persons can also carry out audits on site, in particular persons who have the specialist knowledge outlined in Article 48 of Directive 2001/83/EC or Article 52 of Directive 2001/82/EC. Such persons are considered suitable if they do not have financial or other interests that could influence their neutrality.

Written process instructions are required for release just as for other manufacturing or testing procedures. This is stipulated in Section 4.24, Part I (chapter C.4 Part I Basic Requirements for Medicinal Products) and Section 11.11, Part II (chapter C.5 Part II Basic Requirements for Active Substances used as Starting Materials) of the EU-GMP Guideline. In Section 8.4., it is clearly stated in Appendix 16 to the EU-GMP Guideline that the Qualified Person must have sufficient knowledge of the product and procedures in accordance with Article 48 of Directive 2001/83/EC in order to carry out his or her duties.

It is customary for manufacturing or quality control to be carried out in several levels, and at different locations or different manufacturers if necessary. The complete manufacturing process, with the exception of release, can also be carried out in other units and institutions. The Qualified Person can take into account releases issued by a Qualified Person in accordance with Article 48 of Directive 2001/83/EC or Article 52 of Directive 2001/82/EC in other European member states. However, the Qualified Person remains personally responsible overall for approving placement of the batch on the market (Directive 2001/83/EC, Article 51 para. 3).

List of released products: The Qualified Person in accordance with Article 51 of Directive 2001/83/EC must certify in a consecutive record or a comparable document intended for this purpose that the instructions in Article 51 of Directive 2001/83/EC have been followed for every batch of a drug product before the batch is put into circulation. If subsequent batches are recalled, this must be noted in the record or comparable document.

Release of test preparations

The release of test preparations is based on the German GCP regulation. Manufacturing and test procedures as well as the manufacture and testing of every batch must, for instance, conform to documentation submitted for the approval of clinical investigations. For this purpose, in particular the Qualified Person responsible for the release of test preparations must maintain close contact with the sponsor of the clinical investigations. As with other drug products, test preparations may be approved only if they are manufactured in accordance with regulations. All findings gathered during manufacturing and testing, such as production conditions, the results of in-process control, review of manufacturing documentation and conformity of products with their specifications, including their outer packaging, must, therefore, be taken into account for the release decision (Article 11 para. 3 of Directive 2003/94/EC). In some circumstances, further criteria are listed, in particular under point 40 in Appendix 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products), which should form the basis for the release decision.

Retention samples

The Qualified Person responsible for release must ensure that a sufficient quantity of retention samples from every batch of finished medicinal product is retained for at least one year beyond the expiration date for the purposes of any analytical follow-up testing that may be necessary and for proof of labelling, including the package insert (point 3 in chapter C.6.19 Annex 19 Reference Samples and Retention Samples). The Qualified Person must also ensure that retention samples of every batch of starting materials used for drug product manufacturing are retained for at least two years after a drug product manufactured using these starting materials is released, unless a shorter retention period is specified in the submission file for marketing authorisation. If information is provided in accordance with § 5 of the German GCP regulation in accompanying documentation, the specimens of these accompanying documents must also be retained for each batch.

In accordance with Chapter 1.5 of Part I of the EU-GMP Guideline, the Qualified Person should also ensure that the Product Quality Review (PQR) is compiled correctly and in good time. The PQR is a product-based instrument for assessing the conformity of existing processes and suitability of established specifications with regard to both raw materials and finished products. This assessment serves, on the one hand, to correct errors and, on the other, to enable continual improvement. Another important element of this assessment is the evaluation of the continuous stability studies in accordance with Chapter 6.23 ff. of Part I of the EU-GMP Guideline, which must be made available to the Qualified Person as per Chapter 6.31. For the Qualified Person, this documentation therefore represents an important basis for assessing GMP conformity of the quality assurance system on which the drug product manufacturing process is based.

More specific requirements for the Qualified Person's duties can be found in Appendix 16 of the EU-GMP Guideline (see figure 2.D-3). This appendix deals in particular with the duties of the Qualified Person if a batch release is performed for drug products with different production and control levels that have passed within, partly outside, or entirely outside the European Union (EU) and European Economic Area (EEA). Cases are also listed in which an intermediate product or bulk material is split up between more than one finished product batch.

Figure 2.D-3 Routine duties of the Qualified Person in accordance with Appendix 16 of the EU-GMP Guideline

Routine duties of the Qualified Person in accordance with Appendix 16,
EU-GMP Guideline

1. Ensuring that:

  • Batch and manufacturing meet approval for placing on the market (including the import licence where necessary).
  • Manufacturing was carried out in compliance with the EU good manufacturing practice or, in the case of batches imported from a third country, standards recognised as equal.
  • The most important manufacturing and testing procedures are validated, and the current production conditions and batch production records have been taken into consideration.
  • All discrepancies or planned changes in production or quality control have been approved by the responsible person, in conformity with an established system.
  • All changes that require modifications to the marketing and manufacturing authorisation have been reported to the relevant authorities and authorised by them.
  • All necessary inspections and tests have been carried out, including all additional sampling, checks and inspections necessitated by discrepancies or planned changes.
  • The necessary documentation regarding production and quality control is complete and has been approved by the staff.
  • All audits have been carried out as specified by the quality assurance system.
  • All factors known to the Qualified Person and relevant to batch quality have been taken into account.

2. The Qualified Person should always update his or her knowledge and experience of technical and scientific progress and changes in the quality control procedures in as far as these are relevant to the products to be certificated by him or her.

3. If the Qualified Person has to certificate a product with which he or she is not yet familiar, whether as a result of new product line being introduced or a job change, he or she must first familiarise him or herself thoroughly with this product in order to be able to complete the task.

4. In line with the relevant national regulations, the Qualified Person may be urged to inform the authorities of changes and may have to reapply for marketing authorisation.

If clinical samples are imported from third countries, the importers are subject to certain obligations. In accordance with Article 13, para. 3 of Directive 2001/20/EC, this responsibility is assigned to the Qualified Person acting on behalf of the importer. The Qualified Person acting for an importer must ensure that drug product manufacturing or testing in third countries is at least equivalent to the standards stipulated by the EU for good manufacturing practice and that each batch complies with the approval documents for clinical trial, in particular the drug product specifications. As stated under No. 40 in chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products of the EU-GMP Guideline et al., the Qualified Person will have to satisfy him or herself of this by performing an audit to establish whether manufacturing has been carried out correctly (see figure 2.D-4).

Figure 2.D-4 Batch assessment of clinical samples by the Qualified Person in accordance with Appendix 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products)

Batch Assessment of Clinical Samples in Accordance with Appendix 13,
EU-GMP Guideline

  • Assessment of batch records, including control reports, test reports of in-process controls and release reports, checks for discrepancies or changes
  • Inspection of manufacturing conditions
  • Establishing the validation status for production facilities, manufacturing processes and methods
  • Investigation of completed packages
  • Assessment of the results of all analyses or tests carried out after import
  • Assessment of reports on stability
  • Verification of storage and shipping conditions
  • Assessment of audit reports concerning the manufacturer's quality assurance system
  • Inspection of the manufacturer's manufacturing authorisation for clinical samples or reference samples
  • Consideration of relevant legal requirements for marketing authorisation, GMP standards to be implemented and each official confirmation of compliance with GMP provisions
  • Consideration of all further factors relevant to batch quality

While the manufacturing process for test preparations (as with other drug products) within European Union member states and states contracting with the European Economic Area must meet the standards for good manufacturing practice specified by the EC (Article 13 para. 3 fig. a of Directive 2001/20/EC), manufacturing processes in a third country must be carried out in accordance with standards that are at least equivalent to those of the EU. In addition, the importer must make sure that the manufacturer is authorised to manufacture and test test preparations. A test preparation must also be released by the Qualified Person if it is listed under Article 13 paragraph 3 fig. c of Directive 2001/20/EC as comparator drugs to be used in a clinical investigation (figure 2.D-4).

1.3 Organisational appointment/substitution regulations

As described in the previous chapters, the Qualified Person has various tasks, which span the entire pharmaceutical quality assurance system. In addition to batch-related document checking at the operative level, he or she fulfils duties that extend far into the strategic area of the business and thereby pertain to classic quality assurance or quality management functions. The appointment of the Qualified Person in the business organisation must allow for this extensive range of responsibilities.

As the person responsible subject to public law, the Qualified Person must forge for him or herself a position that is largely independent of the classic structure and process-oriented organisation, since the Qualified Person is not bound by instructions within the context of fulfilling his or her tasks. Ideally, therefore, the Qualified Person is integrated in the quality assurance department, usually in a dual role with the management of this department. A staff position in the upper echelons of the organisational hierarchy would also be possible.

The various duties to be fulfilled by the Qualified Person should be described in a job description in accordance with Article 7 of Directive 2003/94/EC. Figure 2.D-5 shows a sample job description for a Qualified Person (for general requirements for job descriptions, see chapter 2.A Place of work and job descriptions).

Figure 2.D-5 Sample job description for the Qualified Person  

Sample GmbH, Modeltown

Job description

Posting date: 06.09.2005

Page 1 of 4

Description of position

Qualified Person in accordance with Article 48 of Directive 2001/83/EC, lyophisilate area

Name of current job holder (internal identifier)

Dr. Susanne Meier (10-123)

Company address

Sunny Street 4
23456 Modeltown
Tel.: 04991-87654, fax: 04991-87655, e-mail: smeier@sample.de

Department code
Quality Assurance (QA)

Deputy for job holder

Dr. Klaus Mьller, Qualified Person for "Solida"

Supervisor

For all personnel matters such as salary, holiday allowance or internal transfer applications, the position holder reports to the personnel department. On technical and organisational matters, the position holder reports to the Quality Assurance department.
In the context of the Qualified Person's position relating to public law, the position holder acts without instruction and reports directly to company management.

Authority of the position holder

The position holder is authorised to issue instructions to:

  • The secretariat of the QA department on matters of correspondence
  • The Head of the Quality Control on matters of retention sample storage, the Product Quality Review and follow-up stability studies

Authorisations

When acting in the function of Qualified Person, the position holder signs all external correspondence on his or her own authority by adding "Qualified Person for lyophilisate" under his or her signature, and all other written communications with the prefix "By proxy" before the signature.

Job specifications

  • Expert knowledge
  • Very good knowledge and experience in pharmaceutical manufacturing and quality control of aseptic dosage forms, in particular in the area of freeze drying
  • Good knowledge of current EU and FDA GMP regulations
  • Project management experience
  • Reliability
  • Leadership skills
  • Decision-making abilities and assertiveness
  • Pronounced sense of responsibility
  • Business mindset
  • Teamwork and organisation skills
  • Ability to work under pressure and flexibility
  • Very good written and spoken English

This is a full-time position and presupposes that the position holder will fulfil the necessary working hours.

Position objectives

As the Qualified Person, the position holder is responsible for both batch release and the control and release of manufacturing and test documentation. He or she is involved in the monitoring and continual further development of the QA system, including monitoring critical quality parameters as necessary in this context. He or she is responsible for coordinating, preparing, executing and postprocessing inspections by national and international authorities, as well as supplier audits. The Qualified Person is also responsible for organising GMP training (planning, execution, control of success).

Detailed description of duties/functions

R = responsibility for execution/makes the decision

S = shared responsibility

I = remains informed

Responsibility for executing a duty always includes the obligation to inform all affected posts.

Duty

R

S

I

Checking and approving GMP-relevant SOPs

 

X

X

Checking manufacturing and test procedures and records

 

X

X

Making changes to marketing authorisation content

 

X

X

Qualifying equipment used for manufacturing and quality control

   

X

Validating manufacturing, cleaning and test procedures

   

X

Process and plant-specific monitoring of GMP-critical parameters

 

X

X

Inspecting discrepancies

 

X

X

Batch release for placement on the market

X

   

Making entries in the list of released products

X

   

Organising self-inspections

X

   

Organising inspection by the authorities and supplier audits

X

   

Monitoring the storage of retention samples

X

   

Compiling and evaluating the Product Quality Review

X

   

Evaluating the results of the continuous stability studies

   

X

Change control procedures

 

X

X

GMP training

X

   

Handling complaints and recalls

 

X

X

Resource planning with regard to budget and personnel in the "parenterals" area

 

X

X

Production planning and control in the "parenterals" area

   

X

Qualifying new suppliers and contract acceptors, reauditing existing contract acceptors

X

   

Checking customs and legal prerequisites relating to drug products when raw materials, packaging material and drug products are imported or exported

X

   

Other duties

Participation in the company "Global Quality System" project

Personal undertakings

  • Willingness to make domestic and foreign business trips lasting several days
  • Sole responsibility for arranging own further training
  • Annual medical exam by the company medical officer

Reviewed by/on Dr. Manfred Keller (Head of QA), 05. 09. 2005

Approved by/on Sally Sample (Managing Director), 06. 09. 2005

Position holder informed on Dr. Susanne Meier, 06.09.2005

Figure 2.D-6 The position of the Qualified Person

The position of the Qualified Person

  • He or she can be deputised only by other Qualified Persons.
  • He or she may also be Head of Production or Head of Quality Control (not recommended).
  • He or she is not involved in the operational business of manufacturing or quality control but has a supervisory position (recommended).
  • A job description is required (if there is to be more than one Qualified Person, this must include division of responsibilities).

In the event that more than one Qualified Person is involved in a drug product manufacturing process, all Qualified Persons must agree that the QA system on which the process is based complies with GMP. In particular, if more than one Qualified Person is appointed, it is essential for individual responsibilities to be divided clearly by means of job descriptions.

As well as defining responsibilities in the job description for a Qualified Person, top company management must also ensure (by means of instructions, for example) that all company divisions support the Qualified Person in the execution of his or her role: "The holder of a manufacturing authorization shall at least be obliged: ... e) to enable the Qualified Person referred to in Article 48 to carry out his duties, for example by placing at his disposal all the necessary facilities" (Article 46 of Directive 2001/83/EC).

This applies especially to the provision, in full measure and in good time, of information and documents to be assessed by the Qualified Person.

To ensure that the Qualified Person can carry out his or her duties as objectively as possible, many supervisory authorities expect him or her not to be directly involved with drug product manufacturing and quality control. On account of the type of role he or she fulfils, the Qualified Person has a quasi supervisory function, as a result of which carrying out any other function, in particular in a supervised operational area, could be considered subject to a "ban on self-contracting". It is, ultimately, a serious conflict of interest for the Qualified Person if, in a dual role as Head of Production, he or she is responsible for selecting starting materials and for the manufacturing procedure and also, as Qualified Person, has to issue the release for the overall process.

2 Head of Production

2.1 Individual requirements for Head of Production

The requirements for qualifications and practical experience are based on the type of drug product to be manufactured and must be defined in-house. It is important to bear in mind that the fundamental requirement for sufficient Qualified Personnel is already included in Article 7 of Directive 2003/94/EC. This is all the more important for the Head of Production, since he or she has a guarantor function for ensuring that drug products and substances are manufactured and stored in line with modern scientific and technological standards (figure 2.D-7).

Figure 2.D-7 Requirements for the Head of Production

Requirements for the Head of Production

  • Adequate specialist qualifications and practical experience
  • Job description required (if there is to be more than one head of production, this must include division of responsibilities)

The areas subordinate to the Head of Production act as a benchmark for the qualification requirements for this position. The most important areas include the following:

  • Type and volume of the products manufactured
  • Company experience with the processes to be applied
  • Complexity of the manufacturing facilities used
  • Number and qualifications of persons to be supervised

2.2 Areas of Responsibility of the Head of Production

Figure 2.D-8 Areas of responsibility of the Head of Production in accordance with the EU-GMP Guideline

Areas of responsibility of the Head of Production in accordance with the EU-GMP Guideline

  • Ensuring that products are manufactured and stored in compliance with specifications
  • Approving manufacturing instructions and ensuring that these are followed
  • Supervising maintenance, premises and manufacturing equipment
  • Ensuring that the necessary validations for manufacturing procedures are carried out
  • Ensuring that production staff receive the necessary initial and ongoing training
  • Cleaning premises and equipment in the manufacturing area
  • Qualifying premises and equipment in the manufacturing area
  • Validating cleaning processes
  • Ensuring that batch production records are reviewed and signed before they are passed on to the Quality Control department
  • Participating in audits (suppliers, subcontractors)
  • Helping process complaints
  • Compiling relevant operating instructions
  • Maintaining specifications
  • Selecting containers for starting materials and bulk material
  • Change control
  • Participation in the compilation and adaptation of submission files for marketing authorisation
  • Participation in environmental monitoring
  • Participation in self-inspections

The main task of the Head of Production is to ensure that manufacturing operations are carried out in line with the written instructions and operating procedures (manufacturing instructions) that have been drawn up previously. Manufacturing must conform to good manufacturing practice as well as accepted pharmaceutical regulations (Article 46 f of Directive 2001/83/EC) (see figure 2.D-8).

The Head of Production's scope of responsibilities and duties must be defined in writing in job specifications in accordance with Article 7 of Directive 2003/94/EC (see Chapter 2.A Place of work and job descriptions). Figure 2.D-9 gives a sample job description for the Head of Production.

If the holder of the manufacturing authorisation has appointed more than one Head of Production, the individual areas of responsibility must be clearly defined and distinguished from one another. If such a distinction is not made, all persons have equal responsibility for the entire manufacturing facility.

The holder of the manufacturing authorisation must help the Head of Production carry out his or her duties by making the necessary organisational, personnel and material arrangements to enable the Head of Production to fulfil his or her role in full.

The Head of Production and the Head of Quality Control must be independent from one another. (Article 11 of Directive 2003/94/EC) (figure 2.D-9).

Figure 2.D-9 Sample job description for the Head of Production (cont.)

Sample GmbH, Modeltown

Job description

Posting date: 05.07.2006

Page 1 of 4

Description of position : Head of Production

Name of current job holder (internal identifier)

Harry Neumann (20-023)

Company address

Sunny Street 4
23456 Modeltown
Tel.: 04991-87652, fax: 04991-87652, e-mail: hneumann@sample.de

Department code
Dept. Production, "Solid Dosage Forms" subdivision

Deputy for job holder

Dr. Gert Klawitter, "Liquida" subdivision

Supervisor

For all personnel matters such as salary, holiday allowance or internal transfer applications, the position holder reports to the personnel department.
On technical and organisational matters, the position holder reports to the head of the Production department.
In the context of the Head of Production's position relating to public law, the position holder acts without instruction and reports directly to company management.

Authority of the position holder

The position holder is authorised to issue instructions to staff in the "Solid Dosage Forms" subdivison as well as warehouse and engineering staff.

Authorisations

The position holder signs external correspondence with the prefix "By proxy".

Job specifications

  • Very good knowledge and several years' experience in pharmaceutical production of solid dosage forms incl. relevant in-process controls
  • Good knowledge of current EU and FDA GMP regulations
  • Basic business knowledge
  • Reliability
  • Leadership skills
  • Decision-making abilities and assertiveness
  • Pronounced sense of responsibility
  • Business mindset
  • Teamwork and organisation skills
  • Ability to work under pressure and flexibility
  • Very good written and spoken English

Position objectives

To ensure that the drug products (in this case, solid dosage forms) are manufactured and stored properly in accordance with regulations under drug product laws as well as EU and USA GMP regulations.

Detailed description of duties/functions

Detailed description of duties/functions

R = responsibility for execution/makes the decision

S = shared responsibility

I = remains informed

Responsibility for executing a duty always includes the obligation to inform all affected posts.

Duty

R

S

I

Checking, approving and regularly updating manufacturing instructions as well as the necessary operating instructions

X

   

Checking and signing batch production records

X

   

Making changes to marketing authorisation content

 

X

X

Qualifying suppliers of starting and packaging materials

 

X

X

Ensuring that the hygiene status in the area of solid dosage forms complies with GMP, including carrying out environmental monitoring

X

   

Monitoring maintenance, qualification and calibration of the premises and facilities in the area of solid dosage forms

X

   

Validating the manufacturing and cleaning processes in the area of solid dosage forms

X

   

Monitoring to ensure that all personnel in the area of solid dosage forms take part in regular training measures

X

   

Monitoring storage conditions for starting materials, packaging materials, intermediate products, bulk materials and finished goods as well as defective products in the area of solid dosage forms

X

   

Clarifying discrepancies in the area of manufacturing solid dosage forms including operating an error prevention system

X

   

Change control

 

X

X

Fulfilling obligations in accordance with Article 46 c of Directive 2001/83/EC to report significant changes in terms of premises and facilities in the area of solid dosage forms to the relevant authorities.

X

   

Further developing manufacturing technology in the area of solid dosage forms

X

   

Production planning and control

 

X

X

Budget and personnel planning

 

X

X

Self-inspections, customer audits and inspections by the authorities

 

X

X

Providing customer service in the area of solid dosage forms

 

X

X

Personal undertakings

  • Willingness to make domestic and foreign business trips lasting several days
  • Sole responsibility for arranging own further training
  • Annual medical exam by the company medical officer

Reviewed by/on
Dr. Stefan Bach, head of Production department/03. 07. 2006

Approved by/on
Sally Sample (Managing Director), 03.07.2006

Position holder informed on

Harry Neumann, 04.07.2006

3 Head of Quality Control

3.1 Individual Requirements for the Head of Quality Control

The individual requirements for the Head of Quality Control are essentially the same as those for the Head of Production (see chapter 2.1 Individual requirements for Head of Production).

3.2 Areas of Responsibility of the Head of Quality Control

The main task of the Head of Quality Control is to check starting materials, final products and, where necessary, intermediate products in line with written instructions and operating procedures (testing procedures) that have been drawn up previously. The testing must be carried out in conformity with good manufacturing practice and the accepted pharmaceutical regulations. This also applies to containers, external casing, packaging and labelling materials as well as package inserts. The Head of Quality Control's areas of responsibility subject to public law are determined in the EU-GMP Guideline (see figure 2.D-10).

The Head of Quality Control can also delegate quality control procedures to other persons within the unit and, to a limited extent, also to third parties. This is particularly relevant when external testing locations are assigned. Routine tests (in-process tests, end-product controls) should always be carried out by the manufacturer. If the manufacturer does not have the suitable equipment or the necessary personnel for certain special analyses, these can be assigned to appointed companies and institutions. It is important to ensure, however, that the external testing location has the appropriate premises and equipment and is able to perform the tests in line with modern scientific and technological standards. Such tests may include sterility and pyrogen testing, or special pollutant residue analyses. In the Head of Quality Control's areas of responsibility (see figure 2.D-11), he or she often works with other function owners, such as the Head of Production or Qualified Person in accordance with Article 103 of Directive 2001/83/EC.

All areas for which the Head of Quality Control is responsible must be recorded in the job description. It is important to clearly distinguish his or her responsibilities from those of the Head of Production and Qualified Person. Figure 2.D-12 gives a sample job description for the Head of Quality Control.

Figure 2.D-10 Areas of responsibility of the Head of Quality Control in accordance with Chapter 2, Part I of the EU-GMP Guideline

Areas of Responsibility of the Head of Quality Control in Accordance with Chapter 2, Part I of the EU-GMP Guideline

1. Approving or rejecting starting materials, packaging materials and intermediate products

2. Interpreting batch records

3. Approving specifications and instructions for sampling and test procedures, as well as ensuring that these are followed

4. Ensuring that all necessary tests are carried out

5. Approving assignments and monitoring analytical laboratories that become operational during the assignment

6. Supervising maintenance, premises and equipment for carrying out tests

7. Ensuring that the necessary validations for test procedures are carried out

8. Ensuring that testing staff receive the necessary initial and ongoing training

Figure 2.D-11 Other areas of responsibility of the Head of Quality Control in accordance with the EU-GMP Guideline

Other Areas of Responsibility of the Head of Quality Control in Accordance with the EU-GMP Guideline

  • Interpreting test records
  • Cleaning and maintaining premises and equipment in the testing area
  • Qualifying premises and equipment in the testing area
  • Participating in the supplier and subcontractor audits
  • Helping process complaints
  • Approving specifications
  • Approving sampling instructions
  • Change control
  • Stability studies
  • Trend analyses
  • Participating in the compilation and adaptation of submission files for marketing authorisation
  • Participating in environmental monitoring
  • Participating in self-inspections

Figure 2.D-12 Sample job description for the Head of Quality Control  

Sample GmbH, Modeltown

Job description

Posting date: 01.08.2006

Page 1 of 3

Description of position : Head of Quality Control

Name of current job holder (internal identifier)

Siegfried Lьdemann (50-023)

Company address

Sunny Street 4
23456 Modeltown
Tel.: 04991-87656, fax: 04991-87656, e-mail: sluedemann@muster.de

Department code
Dept. Quality control

Deputy for the position holder

Ludwig Koch, dept. Quality Control

Supervisor

For all personnel matters such as salary, holiday allowance or internal transfer applications, the position holder reports to the personnel department.

On technical and organisational matters, the position holder reports to the head of the Quality Control department.

In the context of the Head of Quality Control's position relating to public law, the position holder acts without instruction and reports directly to company management.

Authority of the position holder

The position holder is authorised to issue instructions to the staff of the Quality Control department.

Authorisations

The position holder signs external correspondence within his or her area of responsibility with the prefix "pp".

Job specifications

  • Very good knowledge and several years' experience in the area of pharmaceutical instrumental analytics, microbiology and galenical testing procedures
  • Good knowledge of current EU and FDA GMP regulations
  • Basic business knowledge
  • Reliability
  • Leadership skills
  • Decision-making abilities and assertiveness
  • Pronounced sense of responsibility
  • Business mindset
  • Teamwork and organisation skills
  • Ability to work under pressure and flexibility
  • Very good written and spoken English

Position objectives

Ensuring that the quality of drug products is properly tested in accordance with regulations under drug product laws as well as EU and USA GMP regulations.

Detailed description of duties/functions

R = responsibility for execution/makes the decision

S = shared responsibility

I = remains informed

Responsibility for executing a duty always includes the obligation to inform all affected posts.

Duty

R

S

I

Checking, approving and regularly updating test procedures as well as the necessary operating instructions

X

   

Checking and signing test records

X

   

Making changes to marketing authorisation content

 

X

X

Qualifying suppliers of starting and packaging materials

 

X

X

Environmental monitoring in the manufacturing area

 

X

X

Monitoring maintenance, qualification and calibration of the premises and facilities in the area of quality control

X

   

Validating sampling procedures and analytical methods

X

   

Monitoring to ensure that all personnel in the area of quality control take part in regular training measures

X

   

Monitoring storage conditions for samples, standards and retention samples

X

   

Clarifying discrepancies in the area of quality control including operating an error prevention system

X

   

Change control

 

X

X

Fulfilling obligations to report significant changes in terms of premises and facilities in the area of quality control to the relevant authorities

X

   

Further developing laboratory equipment

X

   

Planning/controlling sample research

X

   

Budget and personnel planning

 

X

X

Self-inspections, customer audits and inspections by the authorities

 

X

X

Customer service in the area of quality control

 

X

X

Providing guidance on questions of occupational health and safety, in particular when staff are handling hazardous substances

X

   

Personal undertakings

  • Willingness to make domestic and foreign business trips lasting several days
  • Sole responsibility for arranging own further training
  • Annual medical exam by the company medical officer

Reviewed by/on

Dr. Manfred Keller (Head of QA), 28.07.2006

Approved by/on
Sally Sample (Managing Director), 31.07.2006

Position holder informed on

Siegfried Lьdemann 31.07.2006

4 Qualified Person in Accordance with Article 103 of Guideline 2001/83/EC

4.1 Individual Requirements for the Qualified Person in Accordance with Article 103

The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must be "suitably qualified". No more details of these qualifications are provided in Directive 2001/83/EC. The national laws of the member states may provide more specific requirements.

The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must be resident in a European Union member state (Directive 2001/83/EC, Article 103).

4.2 Areas of Responsibility of the Qualified Person in Accordance with Article 103 of Directive 2001/83/EC

The Qualified Person in accordance with Article 103 is the person that the pharmaceutical manufacturer assigns to gather and assess information that has emerged about presumed side effects and to coordinate the necessary measures (see figure 2.C-13). His or her area of responsibility is finished medicinal products. A side effect, for the purposes of Article 1 No. 11 of Directive 2001/83/EC, is "A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function."

In line with Article 103 of Directive 2001/83/EC, the Qualified Person in accordance with this article must gather all known reports of presumed side effects, in line with written procedures. The holder of approval for placement on the market is obliged to compile a report of these side effects in accordance with Article 104 of Directive 2001/83/EC. This report is usually delivered electronically.

Information is gathered either by word of mouth or in writing, but also as a result of an active search for information on the part of the Qualified Person, for instance by studying literature or carrying out computer-assisted research. The Qualified Person in line with Article 103 informs the authorities of the member state in which the side effect has occurred. If the side effect is reported in a third country, the European Medicines Agency (EMEA) and the authorities of the member states in which the drug product was approved must be informed. The Qualified Person must also ensure that further information for assessing the risk-benefit ratio of a drug product, including his or her own evaluations, is delivered immediately and in full to the responsible authorities upon request.

The risk-benefit ratio comprises an evaluation of the positive therapeutic effects of a drug product in relation to the risk. Risks may concern the quality, safety or efficacy of the drug product for the patient's health or public health (Article 1 No. 28 of Directive 2001/83/EC). In the case of drug products intended for use on animals, risks to the health of both humans and animals are assessed.

The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must also initiate the review of reports of undesirable effects of drug products and evaluate whether or not this poses a drug product risk. The Qualified Person in accordance with Article 103 of Directive 2001/83/EC is also responsible for ensuring that all complaints are recorded systematically. This includes initiating an immediate review of reports. He or she must coordinate the necessary measures and make the Qualified Person in accordance with Article 48 of Directive 2001/83/EC aware of the issue. This enables the Qualified Person to take the necessary measures in his or her area, in particular if the problem could relate to quality. It is important to check the effectiveness of this procedure on a regular basis, for instance as part of the self-inspection or simulated product complaints and recall actions.

When reviewing and evaluating the reports, the Qualified Person in accordance with Article 103 of Directive 2001/83/EC should receive the support of the Heads of Production and Quality Control and the Qualified Person whose areas of responsibility are otherwise unaffected.

The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must inform the responsible authorities immediately of every deficiency that could lead to a recall or an abnormal distribution limitation, and also notify them of the states in which the drug product has been placed on the market or implemented. Furthermore, the authorities must be informed immediately of any reasonable suspicion of counterfeit medicinal products (Article 13 para. 1 of Directive 2003/94/EC) (figure 2.D-13).

Figure 2.D-13 Areas of responsibility of the Qualified Person in accordance with Article 103 of Directive 2001/83/EC

Areas of Responsibility of the Qualified Person in Accordance with Article 103 of Directive 2001/83/EC

  • Gathering reports of drug product risks
  • Assessing drug product risks
  • Monitoring clinical trials relating to drug product risks
  • Reporting serious side effects, informing the supervisory authorities in the event of abnormal distribution limitations (for instance, delivery stop, recall)
  • Defining and coordinating measures for risk aversion
  • Record keeping

The requirements stated in Article 123 para. 2 of Directive 2001/83/EC must be taken into account for every recall: "The marketing authorisation holder shall be obliged to notify the Member States concerned forthwith of any action taken by him to suspend the marketing of a medicinal product or to withdraw a medicinal product from the market, together with the reasons for such action if the latter concerns the efficacy of the medicinal product or the protection of public health. Member States shall ensure that this information is brought to the attention of the Agency."

To enable the Qualified Person in accordance with Article 103 of Directive 2001/83/EC to fulfil his or her duties correctly, the pharmaceutical manufacturer must ensure that the Qualified Person in accordance with Article 103 of Directive 2001/83/EC is informed immediately of all reports of drug product risks and provided with the necessary personnel and material resources. This obligation arises from the fact that the organisational power lies with the pharmaceutical manufacturer, who is responsible for ensuring that information flows effectively to all affected departments within the organisation.

5 Scientific Service in Charge of Information

5.1 Individual Requirements for the Scientific Service in Charge of Information

The individual requirements are not described in more detail in Article 98 para. 1 of Directive 2001/83/EC. The only requirement is the formation of a Scientific Service in Charge of Information. These requirements can be substantiated by the national law of the member states.

5.2 Areas of Responsibility of the Scientific Service in Charge of Information

The Scientific Service in Charge of Information in accordance with Article 98 of Directive 2001/83/EC is the person commissioned by the pharmaceutical manufacturer to take on the responsibility of gathering scientific information about the drug product.

In particular, he or she is responsible for ensuring that the ban on providing misleading information regarding drug products in accordance with Article 87 para. 3 of Directive 2001/83/EC is observed.

Misleading information includes the following situations, for example:

  • If drug products are attributed a therapeutic efficacy or effects that they do not possess
  • If the impression is falsely given that a successful result can safely be expected, or that no harmful effects can result from the intended or prolonged use
  • If suitable designations, data or presentations that play a part in the assessment of a drug product are used with the intent to deceive the public with regard to drug product quality

Furthermore, the Scientific Service in Charge of Information must ensure that the labelling, package insert, technical information and advertising correspond to the content of the marketing authorisation or registration.

The concept of "advertising" is defined in Article 86 of the consolidated Directive 2001/83/EC (see figure 2.D-14).

Figure 2.D-14 "Advertising" for the purposes of Directive 2001/83/EC

Advertising for the purposes of Article 86, Directive 2001/83/EC

  • Public advertising for drug products
  • Advertising drug products to persons who are entitled to be prescribed or dispensed drug products
  • Visits by medical sales representatives to persons who are entitled to be prescribed or dispensed drug products
  • Delivery of drug product samples
  • Incentives to prescribe or dispense drug products by means of granting, offering or promising financial or material advantages providing that these are not of marginal value
  • Sponsoring sales promotion events attended by persons who are entitled to be prescribed or dispensed drug products
  • Sponsoring scientific congresses attended by persons who are entitled to be prescribed or dispensed drug products, in particular covering transportation and lodging costs of these persons

The Scientific Service in Charge of Information also takes on tasks arising from Article 98 para. 2 of Directive 2001/83/EC (see figure 2.D-15) on behalf of the authorisation holder.

Figure 2.D-15 Duties of the Scientific Service in Charge of Information in accordance with Directive 2001/ 83/EC

Duties of the Scientific Service in Charge of Information in accordance with Article 98, Directive 2001/ 83/EC

1. The holder of approval for placement on the market establishes a scientific post within his or her organisation that is assigned the task of providing information on the drug products that the approval holder puts into circulation.

2. The holder of approval for placement on the market:

  • Keeps a copy of every advertising text circulated by his or her organisation, as well as a data sheet specifying the recipient, distribution type and date of first distribution available for the authorities or posts responsible for control of pharmaceutical advertising, or delivers these texts to such authorities
  • Makes sure that the pharmaceutical advertising carried out by his or her organisation complies with this title
  • Checks whether the medical sales representatives employed by his or her organisation are properly trained and fulfilling their obligations as per Article 93 paragraphs 2 and 3
  • Provides the authorities or posts charged with controlling pharmaceutical advertising with the information and assistance that they require in order to carry out their task
  • Ensures that the instructions given by the authorities or posts responsible for controlling pharmaceutical advertising are followed promptly and in full

The function of the Scientific Service in Charge of Information is part of the preventative consumer protection scheme insofar as it generally ensures that only information covered by the authorisation is enclosed with a drug product. The Scientific Service in Charge of Information acts in a preventative manner to avoid information deficits, while the Qualified Person in accordance with Article 103 of Directive 2001/83/EC must intervene retrospectively once an information deficit has occurred.

6 Medical sales representatives

6.1 Individual requirements for medical sales representatives

Medical sales representatives must, in accordance with Article 93 para. 1 of Directive 2001/83/EC, have appropriate training and sufficient knowledge to enable them to give precise and as complete as possible information about the drug products they offer. Individual member states can specify additional requirements.

The pharmaceutical manufacturer's Scientific Service in Charge of Information should check regularly whether the medical sales representatives are sufficiently qualified to perform their duties correctly. As outlined in figure 2.D-15, this obligation arises from Article 98 para. 2 of Directive 2001/83/EC.

6.2 Areas of responsibility of the medical sales representative

The medical sales representative acts as a conveyor of information between the pharmaceutical manufacturer and members of the healing professions (see figure 2.D-16). He or she has to provide them with specialist information about drug products for the purposes of Article 1 No. 2 of Directive 2001/83/EC. This task can be carried out in person on site, or by telephone. When giving advice about individual drug products, the medical sales representative must present the corresponding technical information. It is essential for members of the healing profession to have access to the scientific results of drug product research and to be able to view them objectively and critically so that they can use, in particular, newly-developed drug products in the correct manner. Due to his or her constant personal contact with the healing professions, the medical sales representative has an important role to play.

It is his or her duty to record any information given by members of the healing processions regarding side effects and contraindications or other risks, and to report these in writing to his or her contract giver, the pharmaceutical manufacturer.

If the medical sales representative is instructed by the pharmaceutical manufacturer to dispense drug product samples, he or she must keep a record of the recipients of these samples as well as the type and volume of the samples and when they are dispensed. These records are subject to monitoring by the authorities.

The medical sales representative must ensure that the quality of the drug product samples is not compromised during storage in the warehouse or transportation, and that the samples are not accessible to unauthorised persons (figure 2.D-16).

Figure 2.D-16 Medical sales representatives in accordance with Article 93 of Directive 2001/83/EC

The "Medical Sales Representative" in Accordance with Article 93 of Directive 2001/83/EC

  • Medical sales representatives must receive appropriate training from their respective employer and have sufficient knowledge to enable them to give precise and as complete as possible information about the drug products they offer.
  • Every time a medical sales representative visits a member of the healing professions, he or she must give a summary of the qualities of each drug product offered including the new information on the sales price and refund conditions for the purposes of Article 91 paragraph 1, if this is permitted under the laws of the member state in question.
  • Medical sales representatives must present to the scientific post stated in Article 98 paragraph 1 all information pertaining to the application of the drug products they are advertising, in particular regarding undesirable side effects of which they have been informed by the members of the healing professions whom they have visited.

Summary

To ensure drug product safety, legislators have transferred duties and responsibilities to certain function owners. The individual prerequisites and areas of responsibility are described in pharmaceutical law.

These include

  • The Qualified Person
  • Head of Production
  • Head of Quality Control
  • Qualified Person in accordance with Article 103 of Directive 2001/83/EC and the Scientific Service in Charge of Information

Written job descriptions containing clear areas of responsibility must be compiled.

Since the duties of the Qualified Person are extensive and to avoid conflicts of interest, the Qualified Person should work within the area of quality assurance and not attend to any operational business in manufacturing or quality control. The Qualified Person can be substituted only by another Qualified Person. More than one Qualified Person may be appointed if their responsibilities are clearly divided in writing.



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