Most Important Definitions In Clinical Trials.

Most Important Definitions In Clinical Trials.



What is Clinical Trials? What are all terms used in Clinical Trials? How ICH Guideline Define all these terms? ICH has mentioned all clinical study related terms in ICH HARMONISED TRIPARTITE GUIDELINE  GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R1)


  • Clinical Trial/Study

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.


  • Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

  • Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).


  • Amendment (to the protocol) See Protocol Amendment.

  • Applicable Regulatory Requirement(s)

 Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.

  • Approval (in relation to Institutional Review Boards)

The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.


A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

  • Audit Certificate

A declaration of confirmation by the auditor that an audit has taken place.

  • Audit Report

A written evaluation by the sponsor’s auditor of the results of the audit.

  • Audit Trail

Documentation that allows reconstruction of the course of events.

  • Blinding/Masking

 A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

  • Case Report Form (CRF)

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

  • Clinical Trial/Study Report

A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).


  • Comparator (Product)

An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.


  • Compliance (in relation to trials)

Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.


  • Confidentiality

Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity.


  • Contract

A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.


  • Coordinating Committee

A committee that a sponsor may organize to coordinate the conduct of a multicentre trial


  • Coordinating Investigator

An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial.


  • Contract Research Organization (CRO)

A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions.


  • Direct Access

Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor’s monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary information.

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.

  • Essential Documents

 Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial).

  • Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

  • Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)

An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.

  • Impartial Witness

A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.


  • Independent Ethics Committee (IEC)

An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.


  • Informed Consent

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

  • Inspection

The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). 1.30 Institution (medical) Any public or private entity or agency or medical or dental facility where clinical trials are conducted.


  • Institutional Review Board (IRB)

An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.


  • Interim Clinical Trial/Study Report

A report of intermediate results and their evaluation based on analyses performed during the course of a trial.


  • Investigational Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.


  • Investigator

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator


  • Investigator / Institution

An expression meaning “the investigator and/or institution, where required by the applicable regulatory requirements”.


  • Investigator’s Brochure

A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).


  • Legally Acceptable Representative

An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical trial.


  • Monitoring

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).


  • Monitoring Report

A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.


  • Multicentre Trial

A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.


  • Nonclinical Study

Biomedical studies not performed on human subjects.

  • Opinion (in relation to Independent Ethics Committee)

The judgment and/or the advice provided by an Independent Ethics Committee (IEC).


  • Original Medical Record See Source Documents.


  • Protocol

A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.


  • Protocol Amendment

A written description of a change(s) to or formal clarification of a protocol.

Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).

  • Quality Control (QC)

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.


  • Randomization

The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.


  • Regulatory Authorities

Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections  These bodies are sometimes referred to as competent authorities.


  • Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)

Any untoward medical occurrence that at any dose: – results in death, – is life-threatening, – requires inpatient hospitalization or prolongation of existing hospitalization, – results in persistent or significant disability/incapacity, or – is a congenital anomaly/birth defect (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).


  • Source Data

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).


  • Source Documents

Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).


  • Sponsor

An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial


  • Sponsor-Investigator

An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

  • Standard Operating Procedures (SOPs)

Detailed, written instructions to achieve uniformity of the performance of a specific function.


  • Subinvestigator

Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.


  • Subject/Trial Subject

An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.


  • Subject Identification

Code A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial related data.


  • Trial Site

The location(s) where trial-related activities are actually conducted.

  • Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).


  • Vulnerable Subjects

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.


  • Well-being (of the trial subjects)

The physical and mental integrity of the subjects participating in a clinical trial.


Reference :-




Current Step 4 version

dated 10 June 1996

What is Minimum Requirements of EU Agencies from Production section of Manufacturing site.?

Minimum Requirements in  Production section  for EU authorized Human Pharmaceutical products manufacturing site as per Eudralex Volume 4  part 1 Chapter 5: Production. 



Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations.



  • Production should be performed and supervised by competent people.
  • All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.
  • All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled with the prescribed data.
  • Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department.
  • Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution.
  • Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.
  • All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation.
  • Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.
  • Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.
  • At every stage of processing, products and materials should be protected from microbial and other contamination.
  • When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials.
  • At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production.
  • Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean).
  • Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.
  • Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control department when appropriate.
  • Access to production premises should be restricted to authorised personnel.


Prevention of cross-contamination in production


  • Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described below and in Chapter 3 can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products.
  • Contamination of a starting material or of a product by another material or product should be prevented. This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and products in process, from residues on equipment, and from operators’ clothing should be assessed. The significance of this risk varies with the nature of the contaminant and that of the product being contaminated. Products in which cross-contamination is likely to be most significant are those administered by injection and those given over a long time. However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination.
  • Cross-contamination should be prevented by attention to design of the premises and equipment as described in Chapter 3. This should be supported by attention to process design and implementation of any relevant technical or organizational measures, including effective and reproducible cleaning processes to control risk of cross-contamination.
  • A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a
  • segregated, self contained production area within a multiproduct facility, where justified.
  • The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following:
  • Technical Measures
  1. Dedicated manufacturing facility (premises and equipment);
  2. Self-contained production areas having separate processing equipment and separate heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate certain utilities from those used in other areas;
  3. Design of manufacturing process, premises and equipment to minimize opportunities for cross-contamination during processing, maintenance and cleaning;
  4. Use of “closed systems” for processing and material/product transfer between equipment;
  5. Use of physical barrier systems, including isolators, as containment measures;
  6. Controlled removal of dust close to source of the contaminant e.g. through localised extraction;
  7. Dedication of equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools;
  8. Use of single use disposable technologies;
  9. Use of equipment designed for ease of cleaning;
  10. Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area;
  11. Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;
  12. Use of automatic clean in place systems of validated effectiveness;
  13. For common general wash areas, separation of equipment washing, drying and storage areas.


  • Organisational Measures

  1. Dedicating the whole manufacturing facility or a self contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness;
  2. Keeping specific protective clothing inside areas where products with high risk of cross-contamination are processed;
  3. Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk;
  4. Depending on the contamination risk, verification of cleaning of non product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer;
  5. Specific measures for waste handling, contaminated rinsing water and soiled gowning;
  6. Recording of spills, accidental events or deviations from procedures;
  7. Design of cleaning processes for premises and equipment such that the cleaning processes in themselves do not present a cross-contamination risk;
  8. Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas;
  9. Use of common general wash areas on a campaign basis;
  10. Supervision of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls.
  • Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures.




  • Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded.
  • When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.
  • Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process, should be validated.
  • Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.

Starting materials

  • The selection, qualification, approval and maintenance of suppliers of starting materials, together with their purchase and acceptance, should be documented as part of the pharmaceutical quality system. The level of supervision should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product. The supporting evidence for each supplier / material approval should be maintained. Staff involved in these activities should have a current knowledge of the suppliers, the supply chain and the associated risks involved. Where possible, starting materials should be purchased directly from the manufacturer of the starting material.
  • The quality requirements established by the manufacturer for the starting materials should be discussed and agreed with the suppliers. Appropriate aspects of the production, testing and control, including handling, labelling, packaging and distribution requirements, complaints, recalls and rejection procedures should be documented in a formal quality agreement or specification.
  • For the approval and maintenance of suppliers of active substances and excipients, the following is required:
  • Active substances1

  • Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified. Appropriate measures should be put in place to reduce risks to the quality of the active substance.
  • The supply chain and traceability records for each active substance (including active substance starting materials) should be available and be retained by the EEA based manufacturer or importer of the medicinal product.
  • Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. The holder of the manufacturing authorisation shall verify such compliance either by himself or through an entity acting on his behalf under a contract. For veterinary medicinal products, audits should be conducted based on risk.
  • Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site. The report should fully reflect what was done and seen on the audit with any deficiencies clearly identified. Any required corrective and preventive actions should be implemented.
  • Further audits should be undertaken at intervals defined by the quality risk management process to ensure the maintenance of standards and continued use of the approved supply chain.
  • Excipients

  • Excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the European Commission ‘Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use’.
  • For each delivery of starting material the containers should be checked for integrity of package, including tamper evident seal where relevant, and for correspondence between the delivery note, the purchase order, the supplier’s labels and approved manufacturer and supplier information maintained by the medicinal product manufacturer. The receiving checks on each delivery should be documented
  • If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release.
  • Starting materials in the storage area should be appropriately labelled (see section 13). Labels should bear at least the following information:
  1. The designated name of the product and the internal code reference where applicable;
  2. A batch number given at receipt;
  • Where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);
  1. Where appropriate, an expiry date or a date beyond which retesting is necessary.


When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label.

  • There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6).
  • Only starting materials which have been released by the Quality Control department and which are within their retest period should be used.
  • Manufacturers of finished products are responsible for any testing of starting materials2 as described in the marketing authorisation dossier. They can utilise partial or full test results from the approved starting material manufacturer but must, as a minimum, perform identification testing3 of each batch according to Annex 8.
  • The rationale for the outsourcing of this testing should be justified and documented and the following requirements should be fulfilled:
    1. Special attention should be paid to the distribution controls (transport, wholesaling, storage and delivery) in order to maintain the quality characteristics of the starting materials and to ensure that test results remain applicable to the delivered material;
    2. The medicinal product manufacturer should perform audits, either itself or via third parties, at appropriate intervals based on risk at the site(s) carrying out the testing (including sampling) of the starting materials in order to assure compliance with Good Manufacturing Practice and with the specifications and testing methods described in the marketing authorisation dossier;
  • The certificate of analysis provided by the starting material manufacturer/supplier should be signed by a designated person with appropriate qualifications and experience. The signature assures that each batch has been checked for compliance with the agreed product specification unless this assurance is provided separately;
  1. The medicinal product manufacturer should have appropriate experience in dealing with the starting material manufacturer (including experience via a supplier)
  2. including assessment of batches previously received and the history of compliance before reducing in-house testing. Any significant change in the manufacturing or testing processes should be considered;
  3. The medicinal product manufacturer should also perform (or via a separately approved contract laboratory) a full analysis at appropriate intervals based on risk and compare the results with the material manufacturer or supplier’s certificate of analysis in order to check the reliability of the latter. Should this testing identify any discrepancy then an investigation should be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier should be discontinued until these measures are completed.
  • Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.
  • Each dispensed material and its weight or volume should be independently checked and the check recorded.
  • Materials dispensed for each batch should be kept together and conspicuously labelled as such.


Processing operations: intermediate and bulk products

  • Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.
  • Intermediate and bulk products should be kept under appropriate conditions.
  • Critical processes should be validated (see “Validation” in this Chapter).
  • Any necessary in-process controls and environmental controls should be carried out and recorded.
  • Any significant deviation from the expected yield should be recorded and investigated.


Packaging materials

  • The selection, qualification, approval and maintenance of suppliers of primary and printed packaging materials shall be accorded attention similar to that given to starting materials.
  • Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure.
  • Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.
  • Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.


Packaging operations

  • When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.
  • Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.
  • The name and batch number of the product being handled should be displayed at each packaging station or line.
  • All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the Packaging Instructions.
  • Containers for filling should be clean before filling. Attention should be given to avoid and remove any contaminants such as glass fragments and metal particles.
  • Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur.
  • The correct performance of any printing operation (for example code numbers, expiry dates) to be done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals.
  • Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are normally preferable to cut-labels, in helping to avoid mix-ups.
  • Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.
  • Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.
  • On-line control of the product during packaging should include at least checking the following:
  1. General appearance of the packages;
  2. Whether the packages are complete;
  • Whether the correct products and packaging materials are used;
  1. Whether any over-printing is correct;
  2. Correct functioning of line monitors.
  3. Samples taken away from the packaging line should not be returned.


  • Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation.
  • Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release.
  • Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if un-coded printed materials are returned to stock.


Finished products

  • Finished products should be held in quarantine until their final release under conditions established by the manufacturer.
  • The evaluation of finished products and documentation which is necessary before release of product for sale is described in Chapter 6 (Quality Control).
  • After release, finished products should be stored as usable stock under conditions established by the manufacturer.


Rejected, recovered and returned materials

  • Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel.
  • The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing.
  • The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.
  • The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department.
  • Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded.


Product shortage due to manufacturing constraints

  • The manufacturer should report to the marketing authorisation holder (MAH) any constraints in manufacturing operations which may result in abnormal restriction in the supply. This should be done in a timely manner to facilitate reporting of the restriction in supply by the MAH, to the relevant competent authorities, in accordance with its legal obligations4.

Reference :- 

The Rules Governing Medicinal Products in the European Union
Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use
Part 1
Chapter 5: Production”