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News and Events:

Official requirements

 

Here you will find answers to the following questions:

  • What legal requirements exist in relation to the documentation?
  • What are the requirements for the documentation according to the EU GMP Guideline?
  • Which documents are relevant to GMP?
  • Which formal aspects must be observed in relation to documents?
  • How should documents be structured?
  • How are documents to be managed and reviewed?

GMP-requirements managed and reviewed according to german pharma business regulations

According to Section 1a of the pharma business regulation, documentation is an essential element of the pharmaceutical quality assurance system. The planning, management and analysis of medicinal product quality are detailed in the quality documentation and they are generally regulated in the form of a quality assurance manual (QA instruction manual). The aim of the quality assurance system is to ensure that the responsibilities for preparation, review and approval as well as regular checks of the documents are clearly established.

Specific documents are requested at various points in the pharma business regulations:

  • Job descriptions and organisational diagrams should be prepared in the area of personnel.
  • Operating rooms must be cleaned and/or disinfected according to a written sanitation programme.
  • Hygiene programmes for hygienic way og acting during the production/analysis of medicinal products should be prepared.
  • Production should be carried out on the basis of manufacturing instructions and documented in a batch record.
  • The qualitiy control should be carried out on the basis of a testing procedure and documented in a test report.
  • Records must be kept on the husbandry of animals used for production/analysis.
  • Regarding contract manufacture and/or analysis written contracts between contract giver and contract acceptor should be concluded.
  • Records must be kept on the acquisition, import, export, storage and marketing of medicinal products.
  • Records on the risks of medicinal products must be kept by the drug safety manager.
  • Records of self-inspections and subsequent corrective actions must be prepared and stored.

All operating procedures relevant to the acquisition, production, quality control, storage, import or export and marketing of medicinal products must be comprehensively recorded. This also applies to records kept on the husbandry of animals, and records kept by the drug safety manager: this means that documentation is mandatory for all important sequences at a pharmaceutical company. The aim of this regulation is to make it possible to fully trace the manufacturing history of a medicinal product from the initial stages until it reaches the consumer.

The records must be clear and unambiguous, free of errors and up to date. According to the regulation, records may be instructions (such as directions, SOPs, plans) as well as records in the stricter sense (such as protocols or reports on tasks undertaken). The following chapter entitled "Formal requirements" shows how the formal requirements can be satisfied.

The handling of corrections in records is of particular importance (see figure 15.A-1). If changes to records are made, it should still be possible at a later date to tell what the original content of the entry was. The use of Tipp-Ex®, overwriting, pasting-over or any other means of rendering entries illegible is therefore not permitted. If it is necessary to correct entries, the original entry should be scored through in such a manner that it remains legible. The accompanying correction should be written in such a way that it can be identified as belonging to the original entry. The signature/initials of the person who made the correction together with the date and possibly the reasoning behind the correction are also required.

Figure 15.A-1 Carrying out corrections

Link to 15.A-1.jpg

Figure 15.A-2 shows a summary of the requirements of the pharma business regulations in relation to the documentation.

Figure 15.A-2 German requirements to the documentation

German requirements to the documentation

  • Completeness
  • Free of errors
  • Clarity
  • Unambiguity
  • Up-to-dateness
  • Corrections properly carried out
  • Electronic data available
  • Electronic data protected from damage and loss
  • Use of electronic signature accompanied by authorisation and security procedure
  • Fast research possible in event of recall campaigns
  • Retention for at least five years

Records may also be certificates where they contain evidence intended for legal use. As a basic rule, the alteration of certificates by any person other than the issuer of the certificate is not permitted. Your attention is drawn to the possibility of prosecution in relation to the manufacturing for fraudulent purposes of false certificates, or the falsification of genuine certificates.

Records may be prepared using computer-assisted systems. Photographic methods (such as microfilming), although somewhat dated, are permissible as a rule. Data stored must be protected from loss and damage throughout the entire storage period irrespective of the storage medium used. Data must be accessible throughout the storage period and it must be possible to make this data readable within a reasonable period of time. As a prerequisite therefore, the operator of these types of systems must have access to the necessary hardware and software or corresponding reading devices in order to be able to access archived (i.e. historical) data at any time and make them readable within a reasonable time period. The regulations do not provide a further indication of when a time period may be regarded as being "reasonable". The guiding principle for the operator of the aforementioned systems should be that any changeover to digital or photographic systems from paper documentation must not lead to increased research times. All marketing records must be organised in such a way that the product can be recalled without delay. A few of the aspects that must be considered are the choice of a suitable data medium, the definition of a data type that will still be readable in the following years, the storage of backup data under suitable physical conditions and the availability of the hardware required to read the data.

For automatic processing of data using computer-assisted systems the reproduction of the name of the head of production/quality control (electronic signature) on the production/test report, as opposed to an original signature, is permitted. The prerequisite for the use of an electronic signature is that "... a suitable approach is taken to ensure that only authorised persons are able to confirm in the batch processing record and test report that manufacturing and analysis have been correctly carried out...".

The following procedures may be considered to be acceptable according to the regulations:

  • combination of a physical key (e.g. chipcard) with a software key (personal password)
  • additional identification for authorised access with additional software key that must be entered each time a batch is released
  • a validated, biometric procedure

All procedures should be defined with regard to the provision of electronic signatures, particularly stand-in arrangements. It should be possible only for the person responsible for release or an authorised stand-in to make changes to the data saved once the batch has been released. The original data must be retained by the system in a comprehensible form.

As a general rule, records must be retained for up to one year after the expiration date and for not less than five years. Records for blood preparations, serum from human blood and genetically-engineered plasma proteins for the treatment of haemostatic dysfunctions must be retained for at least fifteen years. If these records are retained or saved for longer than thirty years they must be made anonymous

Requirements of the EU GMP Guideline

Chapter 4 of the EU GMP Guideline is entirely devoted to documentation: this reflects the great importance of this topic in pharmaceutical operations. The basic principles contained in the german regulations referred to above are also to be found here.

The EU GMP Guideline argues that clearly written and unambiguous documents prevent verbal communication errors and make it possible to trace the history of a batch. The batch documents are therefore the most important records in terms of providing evidence of medicinal product quality. Where the terms "manufacturing instructions/batch production record" and "testing procedure/test report" are used in the pharma business regulations to refer to the overall batch documents, the EU GMP Guideline refers to "batch production records" and "processing instructions", "packaging instructions", "records of batch manufacturing", "records of batch packaging" as well as "process descriptions" for analysis and sampling.

To prevent misunderstandings, the terms should be applied uniformly. If the manufacturer decides to use different terms for the batch documentation, their meaning should be clarified by an index of synonyms. The most important contents of the manufacturing and test documents are presented in figure 15.A-3 and figure 15.A-4. Consult chapter 15.C Batch documentation for more detailed information.

Figure 15.A-3 Contents of manufacturing instructions and batch processing record

Manufacturing instructions

Batch processing record

  • Medicinal product (item no.)
  • Dosage form, strength, batch size
  • Formulation
  • Equipment to be used
  • Manufacturing procedure
  • In-process testing including limits
  • Labelling/packaging
  • Precautions
  • Medicinal product name/batch no.
  • Manufacturing times
  • Persons involved
  • Initial weighing
  • Manufacturing carried out
  • Results of in-process testing
  • Yield
  • Deviations

Figure 15.A-4 Contents of testing procedure and test protocol

Testing procedure

Test protocol

  • Medicinal product (item no.)
  • Dosage form, strength, batch size
  • Specifications
  • Sampling procedures
  • Testing equipment
  • Analytical procedures including standards and reagents to be used
  • Medicinal product name/batch no.
  • Test results
  • Persons involved
  • Raw data
  • Evaluation of test results
  • Special observations
  • Deviations

Not only the batch documents but also all records that provide evidence that GMP requirements have and will be complied with are relevant to GMP (cp. figure 15.A-5).

Figure 15.A-5 GMP-relevant documentation contents  

Area

GMP-relevant documentation contents

Quality
assurance

  • QA instruction manual
  • Organisation chart and job descriptions
  • Directions and records for self-inspection
  • Validation master plan
  • Change control program
  • Release procedure
  • Contracts for manufacturing on a contract basis

Personnel

  • Training
  • Directions on the examination of personnel
  • Hygiene programmes: personnel clothing and hygiene

Manufacture

  • Calibration/qualification of facilities and equipment
  • Maintenance, repair and cleaning of equipment and facilities (log books)
  • Operating instructions
  • Process and cleaning validation
  • Manufacturing instructions/record
  • Measures in the event of manufacturing deviations
  • Labelling and packaging of containers
  • Sanitation programme for rooms
  • Hygiene programmes for hygienic behaviour
  • Records of environmental monitoring
  • Documentation of storage including receipt
  • Directions on pest control
  • Reports on audits at suppliers and contract manufacturers

Quality control

  • Control of starting materials
  • Sampling procedures
  • Testing procedure/record
  • Procedure for OOS results
  • Calibration/qualification of laboratory equipment
  • Analytical method validation
  • Handling of standards and reagents

Sales

  • Proof of sales
  • Measures in the event of complaints
  • Recall campaign schedules

Evidence, according to ISO 8402:1994, definition 2.19, is information that can be verified as being accurate and is based on facts obtained through observation, measurement, investigation or other ascertainment methods.

A GMP conforming documentation normally consists of documents containing instructions (e.g. process instructions/SOPs, plans) and documents that prove that these instructions have been observed in practise (e.g. records, reports). Instructions must be carefully prepared, reviewed and distributed. Records and reports should always be prepared on the basis of pre-approved instructions.

Changes should only be made once approval has been obtained and these should be made based on a specified procedure. Once a particular documentation has been revised, steps should be taken to ensure that the previous version is not used inadvertently.

Where copies of original documents are made for use as working documents it is particularly important to ensure that the number of copies issued and the recipients are known. Copies must therefore be stamped and issued by the department responsible, e.g. quality assurance. In the event of an update, the recipients must themselves either destroy the previous version, and document this accordingly or make sure that it is returned in order to the issuing department.

Although type and scope of the documents used in a pharmaceutical operation vary considerably, generally applicable requirements may be compiled for all documents to be observed:

Written form: "Anything that has not been written down has not taken place." This principle applies when determining requirements in instructions and logging completed tasks in records. It is irrelevant as to whether records are prepared using typewriters or data processing systems. However, apart from the entry of data, documents should not be handwritten. Handwritten entries should be legible and indelible (pencil must not be used!). It is important that relevant data/information is in fact available directly.

Accuracy: The documentation should be correct. Whenever applicable, the contents should correspond with the submission file for marketing authorisation, the manufacturing authorisation and other higher-level documents, as well as the actual situation on-site. The accuracy of critical data is normally checked according to the principle of dual control, i.e. checked by a second person.

Completeness: All records must be completed with no gaps and retained. It should be possible with little effort to determine whether a document is complete - e.g. by including the total number of pages and a table of contents.

Clarity: The content of documents should be comprehensible and easy to follow - not only for the staff who deal with the documents internally on a daily basis but also for outsiders, such as inspectors or contract givers. The contents of the document should be clear and the title, type and purpose should be clearly indicated.

Up-to-dateness: All records must be up to date. Documents must therefore be compiled on time and adapted as required to cater for any changes in circumstances. Records should be made at the time the relevant operation is carried out.

Availability: The relevant documents must be available to the responsible person on-site and must be usable. The responsible persons must therefore know and understand the document and must be able to use it. They must be informed on time about any changes to the document. If records are created using electronic, photographic or other data processing systems, it must be possible to make these available in legible form within a reasonable time limit.

Approved: Documents must be approved by the relevant responsible person before they are used. A document must be suitable for its intended purpose before it can be approved (accurate, up-to-date, useful).

Electronic documentation systems

The EU GMP Guideline permits the use of computer-assisted systems or photographic systems for the compilation of records (electronic documentation systems). Where computer-assisted systems are used for documentation purposes, the relevant basic principles laid down in chapter 4 of the guideline (chapter C.6.11 Annex 11 Computerised Systems) must still be complied with. Persons in responsible positions should be given suitable training in the planning and use of computer systems within their area of responsibility.

Data should only be entered or changed by authorised persons. The identity of the operator who enters or confirms critical data should be checked by the system. Each change to critical data that has been entered should be specifically authorised and documented together with the reason for the change. To this end, a system should be used that provides a comprehensive record of all entries and changes (audit trail). Suitable measures that protect against unauthorised data entry include the use of keys, identification cards, personal codes, and the restriction of access to computer terminals.

The system should, as required, check that the entry and processing of data is accurate. If critical data is entered manually (e.g. weight and batch number of an active pharmaceutical ingredient during dispensation), the accuracy of this data should be verified by an additional control test. This test could be carried out by a second operator or by using a validated electronic method.

The data should be physically or electronically protected against wilful and/or unintentional damage. The availability, durability and accuracy of saved data should be checked.

Further information is provided in chapter 15.C.3 Electronic batch recording

Formal requirements

The format and organisation of documents should be uniform and they should be written in a comprehensible language. The area of application and purpose of the document must be clearly recognisable and appropriate.

A uniform format increases readability, makes the document more recognisable and enhances familiarity, which in turn increases the level of acceptance. Formatting matters, such as font type and size, line spacing, paragraph formatting, layout document header and footer, borders or titles, may be determined uniformly in document templates. The format may also be used to differentiate between various document types (e.g. instruction and record).

Figure 15.A-6 Example of a document cover

Sample pharma

Title of document:
Compiling and updating standard operating procedures

Page/pages
1/8

Document number: 01-100

Version: 02

valid from:
01.02.2004

File name/path: U:\QA\Documents\01\Sample.doc

Area of application: the following departments (for example): quality assurance, production, quality control, packaging, research + development

Key words: for researching electronically administered documents (for example)
SOP, standard operating procedure

Replaces version: 01 of: 01.02.2005

Changes made since last version: significant content changes
Chapter 2.2: document structure reviewed

Cross references: further applicable documents
12345-01, 67890-02

References: relevant laws, standards, scientific literature
DIN EN ISO 9001:2000

Distribution list: recipients of document
LH01, LH02, LQK01, FE01, FE02, GF01

Compiled by:
Dr. M. Recorder

on: 16.12.2004

Checked by:
B. Examinus

on: 17.12.2004

Authorised by:
Dr. H. Head

on: 05.01.2005

A logical structure provides a quick overview, increases the speed at which positions in the text can be located and makes the integration of changes easier, thus reducing the time spent working with the document. A method which has proven to be effective is to provide a summary of the document's characteristic data on a cover (cp. figure 15.A-6).

The main part of the document should also be organised uniformly as shown in figure 15.A-7 by way of example. This should quickly enable a reader who is unfamiliar with the document to find his/her way around it.

Figure 15.A-7 Organisation of a document

1. Purpose of the document:

  • Presentation of the objectives pursued by the document

2. Definitions/abbreviations:

  • Explanation of terms and abridgements that are central to providing an understanding of the document

3. Responsibilities:

  • Presentation of the responsibilities for carrying out and participating in the procedures described, as well as the monitoring thereof. If tasks can be delegated, this should be noted specially.
  • Presentation of responsibilities as regards the ongoing maintenance of this document in terms of the revision, checking and approval of contents

4. Procedure:

  • Description of the objective and the tasks that are required to achieve it
  • Specifications for the materials and equipment to be used
  • Acceptance criteria, also dates/time limitations, limits to be complied with
  • Information on documentation, forms or templates to be used
  • If required, information on the action to be taken in the event that deviations occur when the process is underway

5. Appendices:

  • Comprehensive data material such as tables, lists or the contents of provisions that must be frequently updated

The language of the document is the means used by the sender of the document to communicate with the recipient. The understanding of the content and the manner in which this is perceived by the recipient, depends on whether the language is used correctly. Of course this is not simply a question of whether a document is compiled in German, English or French, for example In multinational companies, instructions by the parent company are often adopted directly and staff are expected to be familiar with all nuances of the foreign language - such as the differences in English between "must", "shall", "have to" or "should".

The impact of the language used in a document particularly depends on how it is written, i.e. the style of the document. The correct choice of style depends, amongst other things, on the recipient and the area of application.

This means that an instruction for temporary staff will need to be formulated differently to an instruction for trained specialist personnel, where prior knowledge of the specialised terms and technical context may be assumed.

For higher-level documents that address aspects of corporate strategy, such as quality management guidelines, it may be sufficient simply to explain the objective and then leave the means open by which this is to be achieved. The formulation of the texts will be less specific as a result. At the operational level (manufacturing instructions, for example) detailed specifications on how to achieve the objective are required and the control objective must be presented. These instructions must therefore be precise and clear.

To illustrate, figure 15.A-8 shows a negative example from a sanitation programme. This instruction is imprecise: what are the "usual procedures", how long is "sufficiently long" or "not too long"? The instruction is also ambiguous: What does "apart from disinfect liquid", "should" or "if possible" mean? Explanations of microbial growth for the purpose of providing background knowledge should be given at training events and not here. Instructions must explain what needs to be done, and not why.

Figure 15.A-8 Negative example of the formulation of text in a sanitation programme

"The disinfectants must be diluted from concentrates according to the usual procedure (apart from disinfect liquid). The dilution must be allowed a sufficient time to act to enable microbial reduction to take place. Once the disinfectant has been diluted, these solutions should not be stored for too long if possible as otherwise, microbial growth may occur and one would therefore achieve exactly the opposite effect."

Figure 15.A-9 contains a selection of typical "negative formulations" that often lead to lack of clarity and ambiguity and also shows how these could be formulated more clearly.

Figure 15.A-9 Formulation style in instructions  

Formulations in instructions

incorrect

correct

"long enough", "sufficiently long"

x to y minutes/hours

"if possible" or "as far as possible"

clear description, define exceptions

"where applicable"

specify when the case applies

"in specific cases"

specify when the case applies

"if required"

specify when something is required

"as far as is necessary"

specify what is necessary

"in general", "mainly"

specify the exceptions

"according to the usual procedure"

cross reference to additional applicable instruction(s)

"as required"

Specify when the case applies

"sufficient"

quantity or time specified including permissible tolerances

following lists: "and so on", "etc."

exhaustive list

"should be", "ought to be", "could"

"is to be", "must be", "must be in such a way"

"one"

responsible person clearly named

double negation

simple affirmation

long, convoluted sentences

short, precise formulations

The area of application and aim of the document must be recognisable, as these aspects determine where the document is to be used and for what purpose. In practice, it is often difficult to formulate these clearly, and also to differentiate between them. For example: if a person drives a car, the "area of application" is clearly recognisable as road traffic. The purpose of the car journey however, may vary: weekend shopping, a visit to relatives, or the daily commute. A similar situation applies in the pharmaceutical sector. The aim of a document and its area of application are not necessarily mutually definable. Where one of these aspects is not clearly formulated, there is room for interpretation by the reader and therefore a danger that the document will be misconstrued.

Provisions regarding the area of application and the aim of a document must always be made within the context of further applicable documents.The area of application of documents should be as wide as possible to make their applicability flexible. The area of application is given where the calibration of a pH meter is to be regulated using a document for example. However, do general provisions, that deal with the handling of calibrating equipment or a calibration documentation type, have to be addressed in this instruction? Would it not be more logical to determine these at a higher level thus providing uniform provisions with a wider area of application? The following basic principle applies: if general provisions can be made, these should be laid down in generally applicable documents. Specific provisions are only necessary for special situations. The repetition of generally applicable procedures in specific instructions unnecessarily increases the quantity of paper used, makes it difficult to maintain an overview and makes it harder to carry out revisions in the documentation.

Management and revision documentation

In order to administer the vast number of documents in a pharmaceutical company, a hierarchical structuring of the document system in three levels (cp. figure 15.A-10) is useful:

Figure 15.A-10 Organisation of a documentation system

Link to 15.A-10.jpg

Strategic level: Documents at this level describe cross-company objectives. Typical examples are the quality management policy and the quality management handbook. The highest level of company management determines this procedure itself and also authorises it.

Operational, cross-company level: The quality policy defined at the highest level should be applied across the company in the form of (standard) process instructions. Documents at this level therefore apply to all departments, or across the company, and are generally not product-related. However, they already include the detailed provisions required in order to implement the objectives defined in documents at the strategic level.

Detailed level: This level contains detailed provisions such as manufacturing instructions, test procedures or sanitation programmes for specific products, procedures or areas. These are compiled on-site on the basis of higher-level instructions (e.g. procedure for the compilation of instructions).

As is the case with facilities, equipment or procedures, documents must also be adapted to accommodate changing operational, scientific and regulatory requirements. A document will pass through a number of typical stages in its life cycle (cp. figure 15.A-11) that reflect the current status of a document. The document should be handled at each stage in accordance with established requirements to ensure that it is suitable for its intended purpose.

Figure 15.A-11 Life cycle of a document

Compilation and changes:  New documents should only be compiled and existing documents should only be changed by the person who deals in practise with the provisions in the document and is familiar with the procedure concerned.

Analysis: Once the above has been carried out, the form and content of the document must be analysed. The formal analysis to verify compliance with the organisational and format requirements (cp. chapter 15.A.3 Formal requirements) can be carried out by the quality assurance department. The technical check should be carried out independently of the compiler by a person who has the appropriate technical knowledge and experience to evaluate the provisions set out by the compiler.

Implementation: GMP-relevant documents must be formally approved before use. This approval should be carried out by the person who is responsible for the area regulated by the document - examples being the head of production or the head of quality control. The start and end of the document's period of validity must be defined independently of the approval. Where no specifications are made in this regard, the document's period of validity is unlimited and begins automatically on the day it is implemented/approved.

Training: In order to be able to implement the contents of the documents, the relevant staff must know, understand and also be able to apply them. These requirements must be acknowledged by signature. Managers must check whether training in the handling of the document is required and, if so, arrange for this to be carried out.

Use: The document should be available on-site for the duration of its validity. This may be achieved by using a hardcopy or providing authorised access to a corresponding file in a computer system. Provisions must exist that specify whether personal working copies may be made and passed on to third parties, if required. The procedure used for the distribution of new versions must be defined.

Inspection: Checks should be carried out within the scope of self-inspections to determine whether the documents are being complied with and whether their contents are still up-to-date and suitable.

Invalidation: Documents that become invalid must be withdrawn from current operations by means of a regulated procedure in order to prevent unintentional use of non-valid documents.

Archiving: The national regulations apply for the storage of documents once they have been used.

In addition to requirements in relation to documents, specific prerequisites must also be fulfilled by staff to ensure that the documents are actually "lived out" - i. e. complied with and implemented. Staff must not only know and understand the provisions laid down in the documents, it is also extremely important that they are prepared to implement these and that the required general operating conditions (organisation, resources) exist.

Summary

All operational procedures relevant to the acquisition, production, analysis, storage, import, export and marketing of medicinal products must be recorded in writing - normally in the form of instructions and records.

The minimum formal requirements for the documentation are: written form, accuracy, completeness, clarity, up-to-dateness, approval and availability.

In order to administer the vast number of documents in a pharmaceutical company, the documentation system must be structured hierarchically in a strategic, operational and detailed level.

The compilation of documents and changes to these should be carried out in accordance with established process instructions at all stages.

Manufacturing instructions/batch processing records and test procedures/test reports are the core element of the GMP-relevant documentation and according to public law, the head of production and the head of quality control are responsible for this.



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