GMP, Pharma

Root Cause Analysis for Drugmakers

Hi Everyone

Whenever regulatory authorities anywhere in the world perform an audit of a drug manufacturer, one of their most frequent findings remains the inadequate performance of the investigation of deviations.

Authorities expect stakeholders will carefully investigate deviations to identify non-compliance, intervene and then evaluate the effectiveness of that intervention. Without adequate investigation and root cause analysis (RCA), those stakeholders cannot effectively identify and design successful interventions. In fact, organizations waste millions of dollars every year on ineffective interventions.

A tool such as RCA uses a defined critical analysis approach in evaluating the reason for a deviation or non-conformance.

RCA techniques include brain storming, the “5 whys” and the “fishbone diagram.” Any and all may be used to explore and further examine the causes behind an event. Firms may then use the resulting analysis to identify areas for change, as well as any recommendations and solutions that aim to minimize the likelihood of an event repeating in the future.

Some organizations go so far as to create a corrective and preventive action (CAPA) for every event, although it is not always necessary.

A firm’s primary goals in investigating an incident should include both discovering its cause and ensuring it does not reoccur.

Regulatory authorities place a high value on RCA and CAPA. Indeed, a large number of FDA observations cite inadequate RCA, ineffective investigation and inappropriate CAPA.

When a deviation occurs, whether in the pharmaceutical or any other industry, the responsible firm must undertake an investigation to determine what went wrong and what damage, if any, the product might have suffered. The investigation process should include some specific steps. These include:

  • Notification of the appropriate stakeholders;
  • Containment action;
  • Classification of the event;
  • Decision to investigate;
  • Determination of the root cause or RCA; and
  • Review and approval process.

The effectiveness of the CAPA taken by an organisation marks another key step in the overall RCA. By monitoring the CAPA, an investigative team can determine whether it truly identified an incident’s root cause and then applied the “appropriate fix.”



Temperature Mapping of Storage Areas

Hi everyone

Good evening

Today we are going to discuss how to carry out a systematic mapping procedure in any cold room, freezer rooms or other temperature-controlled store

1.0. Requirements:

All new temperature-controlled storage areas must be temperature-mapped as part of a fully documented verification process, before the installation is commissioned and handed over by the installer.

2.0. The temperature mapping procedures should:

Demonstrate the air temperature profile throughout the storage area, when empty and in a normal loaded condition;

  • Define zones which should not be used for storage of TTSPPs “Time and temperature sensitive pharmaceutical product” (for example areas in close proximity to cooling coils, cold air streams or heat sources); andIf required, demonstrate the time taken for temperatures to exceed the designated limits in the event of power failure.
  • Depending upon the routine monitoring strategy, subsequent mapping exercises may also be required on a periodic basis – for example, every three years – in order to demonstrate continuing compliance.
  • All mapping exercises should be fully documented in order to demonstrate compliance to management, clients and the regulatory authorities.

3.0. A temperature mapping exercise involves a four stage process, as follows:

  • Prepare a mapping protocol.
  • Carry out the mapping exercise
  • Prepare a mapping report.
  • Implement the recommendations by carrying out the remedial and other actions identified in the mapping report. A follow-up mapping exercise may then be needed to verify the effectiveness of the remedial actions.

3.1. The mapping protocol

A detailed and comprehensive protocol should be prepared, reviewed and approved before the mapping exercise begins. A well-designed protocol will help ensure that the mapping study is correctly carried out. With suitable adjustments or options to cover the full range of temperature regimes, a standard protocol can be used to map any storage area in the facility.

3.2. The mapping protocol should contain the following sections:

  • Approval page and change control history.
  • Acronyms and glossary.
  • Description and rational
  • Scope
  • Objectives.
  • Methodology
  • Mapping report template.
  • Annexes as needed, including templates for the mapping report

3.3. Methodology:

  • STEP 1 – select EDLMs:
  • STEP 2 –  designate the mapping team:
  • STEP 3 – survey the site:
  • STEP 4 – establish acceptance criteria:
  • STEP 5 – determine EDLM locations:
  • STEP 6 – record EDLM, monitoring sensors and thermostat locations:
  • STEP 7 – label and program the EDLMs:
  • STEP 8 – fix EDLMs in position:
  • STEP 9 – conduct the mapping exercise:
  • STEP 10 –  download and consolidate the data:

3.4. Mapping report template:

The mapping report should include the following sections:

  • Introduction: a description of the objectives of the mapping study.
  • Summary: a summary and discussion of the results organised in the sequence set out in the mapping protocol, including a summary of deviations (if any).
  • Conclusions and recommendations: a general conclusion for all verification’s and observations indicating the acceptability of the equipment for operating Recommendations and remarks can be incorporated as well.
  • Report annexes: The report annexes should contain the following:
  • The site survey, showing EDLM locations.
  • The raw data, presented using the appropriate test data sheet format
  • Spreadsheet data and related temperature graphs for every EDLM used in the mapping exercise.
  • Raw results of the data analysis, including hot and cold spots.
  • Key documents and notes prepared during the mapping exercise, together with any other supporting material.
  • Deviation reports, including Corrective and Preventive Actions (CAPA) forms, if required. This may include a recommendation for partial or total re-mapping.Calibration certificates for all EDLMs used.

4.0. Implementing the mapping report recommendations:

The final outcome and purpose of a mapping exercise is the implementation of the report recommendations.


  1. Health Canada (HPFB Inspectorate): Guide 0069: Guidelines for temperature Control of Drug Products during Storage and Transportation. October 17, 2005.
  2. IATA. 2013/2014 Perishable Cargo Regulations (ePCR) & Temperature Control
  3. Regulations (eTCR)
  5. PDA Technical Report No. 39: Guidance for Temperature Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. Parenteral Drug Association. 2007.
  6. United States Pharmaceopaedia: Chapter 1079: Good Storage & Shipping Practices.
  7. United States Pharmaceopaedia: Chapter 1118: Monitoring Devices – Time, Temperature and Humidity.
  8. US Food and Drug Administration. Title 21–Food and Drugs. Chapter I–Food and Drug administration Department of Health and Human Services. Subchapter A— General. Part 11 Electronic Records; Electronic Signatures 21 CFR Part 11
  9. WHO Technical Report Series No. 961, 2011, Annex 9: Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical





Hi everyone!

Today we are going to discuss about the CEP/COS (Certification of suitability of European Pharmacopoeia monographs/ Certificate of suitability)!
Before filing a CEP, Let’s have a look about its history.


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European Directorate for the Quality of medicines and Healthcare was established in the year 1992 as a pilot scale and took over charge as a routine procedure in the year 1994 for the chemical substances. It was then expanded in the year 2003 and included herbal drugs and herbal drug preparations.

The aim of the EDQM is to assess whether the relevant European Pharmacopoeia monograph(s) can be used to adequately to control the quality and impurity profile of an API or excipient produced and/or distributed by the manufacturer. The procedure is complemented by an inspection programme of manufacturing and/or distribution sites, involving a network of around 100 assessors and 30 inspectors from 24 different national competent authorities and the EDQM.

Why to file a CEP?

The Certification procedure is not compulsory – it is a service that is offered to the API and excipient manufacturers, who can use a Certificate of Suitability (CEP) in an application for a new market authorisation (MAA) or for a variation of an existing MAA.


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The manufacturer of a substance will be able to provide proof that the quality of the substance is suitably controlled by the relevant monographs of the European Pharmacopoeia by means of a certificate of suitability granted by the Certification Secretariat of the European Directorate for the Quality of Medicines (EDQM) To apply for a certificate a manufacturer will submit a detailed dossier (Refer ICH M4 CTD) which may also contain confidential data.

The procedure is intended to be applied for the assessment of quality with regards to the criteria of the monograph(s) as appropriate.

The certificate of suitability certifies that by applying the relevant monographs of the European Pharmacopoeia, if necessary with an annex appended to the certificate, it is possible to check whether or not the quality of the substance is suitable for use in medicinal products. In other words, it ensures that all possible impurities and contamination from this particular route of manufacture (including source materials), genotoxic impurities, elemental impurities that can be fully controlled.

The CEP certification procedure can be applied for the following substances:

1. Organic or inorganic substances (active or excipients), manufactured or extracted.

2. Substances produced by fermentation as indirect gene products, which are metabolites of microorganisms, irrespective of whether or not the microorganisms have been modified by traditional procedures or r-DNA technology (see the monograph Products of Fermentation).

3. Products with risk of transmitting agents of animal spongiform encephalopathies(TSE)

The certificate of suitability will be delivered in preference to the manufacturer of substances intended for pharmaceutical use. In special cases where the holder will not be the manufacturer but an authorised agent, a formal agreement is required.

The Certification procedure centralises the evaluation of data for the benefit of regulatory authorities and industry alike, thus saving time and resources. For example, on average it takes three days for a regulatory authority to assess an Active Substance Master File (ASMF), which is the document submitted by a manufacturer of a medicine as part of its application for MAA (the ASMF contains complete information on an API or finished drug dosage form). If the CEP included in the ASMF is used in 10 countries, this assessment only needs to be done once, thus saving 27 days and the corresponding resources.
Also, the Certification procedure provides the European Pharmacopoeia Commission with current information on the quality of substances on the European market, thus helping to identify whether or not a revision of specific European Pharmacopoeia monographs is needed.
CEPs – which are referred to in EU pharmaceutical legislation – are recognised by the European Pharmacopoeia member states and by a number of other countries and regions, such as Australia, Canada, New Zealand, Saudi Arabia, Singapore, South Africa, Taiwan and Tunisia. An increasing number of licensing authorities worldwide accept CEPs to support (fully or partially) the data related to the quality of APIs used in medicinal products.
In order for a specific manufacturer to be granted a CEP, the EDQM’s panel of assessors (drawn from national medicines agencies throughout Europe) review a detailed dossier submitted by the manufacturer.
This dossier describes the manufacturing process and the tests performed on the raw materials and on the substance produced, as well as the necessary in-process controls.
The manufacturer must demonstrate that its product complies with the quality standards required by the European Pharmacopoeia and EU legislation and, in particular, that the monograph can be used to control impurities. The applicant must also agree to comply with the relevant Good Manufacturing Practice (GMP) as defined in Part II of the EU GMP Guide, and to accept a site inspection at any time at the request of the EDQM.


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After complete assessment of the CEP, the manufacturer finally receives the CEP certificate, which is valid for 5 years. If there is a change in the manufacturing process or change in the content of the dossier, the CEP can be revised.




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