GMP Question & Answer Guide


GMP Question & Answer Guide
The requirements defined in the GMP Guidelines often leave room for interpretation. However, regulators worldwide (EMA, FDA, TGA etc) sometimes publish frequently asked questions on GMP. In a new ECA document these Q&As are summarized in a single source. The Q&As are structured in 4 main GMP Areas (General GMPs, GMP for APIs, GMP for Medicinal Products, GMP for IMPs). The document contains 150 pages of Q&As and is available at no cost on the ECA Webpage. A first set of ECA Q&As have also been included and additional GMP Q&As are planned for the future. Here you can access the GMP Questions and Answers Guide

GMP Question and Answer Guide „GMP Advisor“
Searching for concrete answers to GMP questions is a time-consuming activity. The document we now offer is intended to provide a single source of information. We have summarized GMP questions and answers from regulators around the world.

In addition to EMA, FDA, Health Canada, MHRA (UK), TGA (Australia) and ICH, we have also used Q&As from ECA. The subject index of the document contains some of the “GMP Key Words” and enables the finding of Q&As addressing the relevant topic. It is intended to update this comprehensive collection and to also add new Q&As once they are available.

The document is structured into the 4 main GMP areas: General GMPs (applicable to medicinal products, APIs and IMPs), GMP for Medicinal Products, GMP for APIs and GMP for Investigational Medicinal Products (IMPs). In addition,it is indicated which organization has issued the Question and Answers. You can access and download the GMP Q&A Guide here

Please see the table of contents below:

1. General GMPs
1.1 EMA Europe
1.1.1 General
1.1.2 EU GMP Annex 1 Sterile Products
1.1.3 EU GMP Annex 6: Manufacture of medicinal gases
1.1.4 EU GMP Annex 8: Sampling
1.1.5 EU GMP Annex 11: Computerised systems
1.1.6 EU GMP Annex 16 QP and Batch Release
1.1.7 EU GMP Annex 19 Reference Standards
1.1.8 Impurities
1.2 MHRA (Europe/UK)
1.2.1Quality Risk Management
1.2.2 Out of Specification
1.3 ECA Academy (Europe)
1.3.1 EU GMP Annex 11: Computerised System
1.4 FDA (USA)
1.4.1 General GMP
1.5 Health Canada
1.5.1 General Issues
1.5.2 Sterile Products
1.6. TGA Australia
1.6.1 General Issues
1.6.9 Reference and retention samples (Annex 19)
1.7 ICH
1.7.1 ICH: Q8, Q9 and Q10
1.7.2 FDA and EMA on Design Space Verification

2. GMP for Medicinal Products
2.1 EU GMP (EMA)
2.2. TAG Australia

2.2.1 Manufacture of sterile medicinal products (Annex 1)
2.2.2 Manufacture of biological medicinal products (Annex 2)
2.2.3 Manufacture of radiopharmaceuticals (Annex 3)
2.2.4 Manufacture of herbal medicinal products (Annex 7)
2.2.5 Sampling of starting and packaging materials (Annex 8)
2.2.6 Qualification and validation (Annex 15)

3. GMP for APIs
3.1 EU GMP (EMA)

4. GMP for IMPs
4.1. EU GMP (EMA)
4.3 TGA Australia

Current FDA’s Warning Letters on IT Topics – Part 2: Finished Medicinal Products and APIs


Current FDA’s Warning Letters on IT Topics – Part 2: Finished Medicinal Products and APIs
In cases of serious deviations from the GMP requirements, the US FDA issues Warning Letters to the companies concerned. In some current Warning Letters from 2014, significant GMP deficiencies with regard to IT topics can be found. Read on.—Part-2-Finished-Medicinal-Products-and-APIs_8457,8366,8308,Z-COVM_n.html

In a first stage of escalation – when serious GMP deviations are identified during inspections, or in case of insufficient corrective measures – the FDA issues a Warning Letter to the companies concerned. Within 15 working days, the companies in question have to undertake concrete action plans to redress those deviations. If these action plans are evaluated as insufficient by the Agency, further escalation levels may follow.

Some Warning Letters from 2014 also list GMP deficiencies with regard to IT topics. Not a single Warning Letter has been exclusively issued just because of IT issues, though. But taken together, all the GMP deviations in a company were so serious that the Agency issued a Warning Letter which also included deviations related to IT.

All in all, 7 Warning Letters from 2014 contain topics with regard to IT. 4 Warning Letters have been issued for manufacturers of medical devices, 2 Warning Letters for manufacturers of medicinal products and 1 Warning Letter for an API manufacturer. In part I of our news on IT-related Warning Letters we covered those regarding medical devices. Following you will find letters with regard to finished medicinal products and APIs.

IT-related Warning Letters on finished medicinal products and APIs

IT-related Warning Letters for manufacturers of finished medicinal products always refer to 21 CFR 211.68 (b): “Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records “21 CFR 211.68 (b)” .

With regard to that area, the Warning Letter issued for the company USV Limited criticises many items and has generally recorded the absence of appropriate provisions for the application of computerised systems. In detail, the following critical points are mentioned:

  • Current computer users in der laboratory were able to delete data from analyses
  • The audit trail function for a GC and a XRD system was disabled at the time of the inspection. Therefore the firm lacks records for the acquisition, or modification, of laboratory data
  • QC lab personnel shared login IDs for HPLC units. The lab staff shared one login ID for the XRD unit. Analysts also shared the username and password for the Windows operating system for the GC workstation and no computer lock mechanism had been configured to prevent unauthorized access to the operation system
  • There was no procedure for the backup and protection of data on the GC standalone workstations
  • In the response the firm lacks assurance that the periodic backed up data include all of the original data generated
  • Also the questions regarding Audit Trails and access controls have been either unanswered or insufficiently answered.

Also the Warning Letter for the company Sun Pharmaceutical Industries lists several critical comments:

  • Numerous deleted raw data files on computers used for the GC instruments in the QC lab. The software on the computers used to control the GC instruments allowed the analysts to delete files from the hard drive with no audit trail or adequate form of traceability in the operating system to document deletion activity
  • The software as configured assigned sequential, numerical names to raw data files within the same folder. When a raw data file was deleted or moved out of the designated folder, the next file recorded into the folder would be saved with an identical name as the deleted file. As a result, data can be manipulated so that saved files appear to be in sequence even if they were not generated sequentially
  • Due to the basic lack of audit trail and data security, an analyst could delete analytical files without traceability – an unacceptable practice from the FDAs point of view

The Warning Letter for the API manufacturer Trifarma doesn’t refer to the respective sections from the CFR. Yet, here again it focused on possible unauthorised manipulation of raw data in the lab. Corresponding provisions were inexistent. Concretely, the following aspects have been addressed:

  • The laboratory systems did not have access controls to prevent deletion or alteration of raw data
  • All laboratory employees were granted full privileges to the computer systems
  • HPLC and GC computer software lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change
  • The response did not describe the audit trails for the processing of the data on your system.
  • The response also states the firm has begun to retain electronic raw data on the local hard drive, but without proper safeguards to ensure they cannot be deleted prematurely

From the authority’s view, the current focus of IT-topics generally concerns the question of data and system security, particularly the traceability of changes by means of Audit Trails.


FDA Warning Letter to USV Limited

FDA Warning Letter to Sun Pharmaceutical Industries

FDA Warning Letter to Trifarma

FDA Warning Letter Homepage

Commentary Regarding new USP Chapters and for Particulate Matter Guidance



Commentary Regarding new USP Chapters and for Particulate Matter Guidance
There are new chapters in the USP regarding testing of subvisible particles. Chapter Subvisible Particulate Matter in Therapeutic Protein Injections <787> became official August 1, 2014. The informational chapter <1787> was developed to support chapter <787> and will be published in USP 38 in November and become official on May 1, 2015. Read more.–787–and–1787–for-Particulate-Matter-Guidance_8398,8427,9086,Z-PEM_n.html

During the current (2010-2015) USP Expert Committee cycle, the Dosage Forms Expert Committee has developed both new and revised general chapters that provide guidance on particulate matter content of injectable drug products. For visible particles, methods are based upon human detection sensitivity as described in Visible Particulates in Injections <790>, which applies to all sterile injectable dosage forms. For subvisible particle content, which is based upon instrumental determination, new particulate matter guidance has been established specifically for sterile injectable biotherapeutic products.

The new general chapter Subvisible Particulate Matter in Therapeutic Protein Injections <787> became official August 1, 2014, and provides an improved version of the approach in the chapter Particulate Matter in Injections <788> for the more-sensitive protein formulations.  Chapter <787> was initiated to modify historical <788> testing by light obscuration, in order to address the sensitivities of protein products. Chapter <787> also provides a testing framework for a scientific and regulatory concern regarding the immunological effects of the sub-10-µm particle load.  In addition, smaller-volume sampling is allowed, down to 0.2-mL aliquots, and sampling of individual containers as well as gentler de-gassing steps is included.  Although particle-size thresholds remain the same at >= 10 µm and >=25 µm, with the same limits as those found in chapter <788>, there is a recommendation to monitor the population below the 10 µm threshold.  Total particle content is limited to 6,000 particles >=10 µm and 600 particles >= 25 µm for all dosage forms.

The new informational chapter Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections <1787> was developed to support chapter <787> and provides sizing, counting, and characterization guidance for all protein therapeutic products; <1787> provides significant expansion of recommended techniques. The new chapter will appear in USP 38 in November and become official May 1, 2015. As an informational chapter, it provides no count limits but instead is focused on the determination of the inherent protein population and its character.

The intent of chapter <1787> is to aid the scientific development process for all therapeutic protein products. The chapter provides guidance on subvisible particles in the 2-µm to 100-µm range. The rationale for using this range is based upon 100 µm as a conservative, lower-limit threshold for visible particles and 2 µm as the lower size domain for which the recommended techniques are considered robust and proven. The informational chapter is presented in three sections: Size and Distribution, Size and Morphology, and Characterization, with descriptions of techniques in each section. Advantages and disadvantages of each technique are presented. The chapter also provides definition and discussion of the three particle categories: a) extrinsic (truly foreign), b) intrinsic (unwanted yet arising from the process or product), and c) inherent (product attribute). A discussion of silicone oil content is included; even though silicone oil is a necessary additive for most products, it may produce artifact counts or unwanted particles, or it may affect the stability of the therapeutic agent if uncontrolled or used in excessive quantity.

It is recommended that data on the population below 10-µm is collected in two data bins:  >= 2-5 µm and >= 5-10 µm. Chapter <1787> concerns all particle species present in the final product; however, it is primarily oriented toward the inherent therapeutic agent condition and acceptability.  Certainly, the acceptability of the therapeutic protein product is dependent upon the innovator data and regulatory review.

D.S. Aldrich, USP Dosage Forms Expert Committee, <787/1787> Expert Panel Chair
D.G. Hunt, USP Dosage Forms Expert Committee Scientific Liaison

Still a GMP problem? Or already a criminal act? Do we need more stringent measures and enforcement in certain situations?

Still a GMP problem? Or already a criminal act? Do we need more stringent measures and enforcement in certain situations?

Sometimes EU and FDA Inspectors discover serious GMP deviations and fraud during an inspection. What are the consequences and do we need to think about additional measures? Please read more in our GMP News.,S-QSB_n.html

When GMP issues are discussed, different interpretations are possible. Sometimes, the implementation of GMP regulations and expectations can be a challenge. However, everyone involved should do his/her best to make sure that GMP has been put in place and that patient safety is ultimately guaranteed.

Now and again, companies may receive GMP Non-Compliance Statements from EU Inspectors or Warning Letters from US FDA Inspectors because of non-compliance issues identified during inspections. This is a serious situation for the companies involved. Organisational problems and frequently also gross mismanagement can be the reasons for these deviations. In most cases companies react professionally to such situations; they identify the underlying root cause and take corrective actions to avoid future problems.

But how to deal with situations where fraud is involved (e.g. Ranbaxy case)? Or when GMP deviations are so serious that they can no longer be just considered as an accidental mistake? Everyone in the GMP environment should be shocked when data have been faked or adulterated, or when not even basic GMP processes have been implemented. How to deal with these companies? Can we already talk about criminal acts?
For example, just a few days ago, the US FDA issued a Warning Letter and an import alert for Marck Biosciences Ltd in India. The content is repulsive and scandalous for the company. The Warning Letter states:  During the inspection, “investigators noted significant mold growth in the washroom located at the entry to the sterile manufacturing area. The ceiling of this room had been allowed to deteriorate to such an extent that it caved in. This room shares a common mezzanine with the adjacent sterile processing rooms.” Moreover, the company faked GMP records and released products to the market which could endanger patient safety. Staff members and management must have known for a long time about the situation. But instead of fixing the problem they neglected these obvious GMP deviations and even lied about the real situation by faking documents.

If FDA or EU Inspectors would identify such a similar issue on their own territory a criminal investigation would be the consequence. Especially when patient safety is at risk or when patients have already been hurt (e.g. Heparin case). But how to deal with companies which are located outside of their territory? Is an import stop still sufficient here? Maybe regulators should think about further actions to be taken against those companies and their management when a GMP deviation can no longer be considered as an accidental error but a criminal act. The information provider Regulatory Focus (RABS) already lists 12 companies in India where serious data integrity issues including faking of documents have been observed. Most of these cases can not be considered as a GMP problem but must be considered as a deliberate adulteration and falsification of data (fraud).

In our GMP News US Regulators may ask CEO to certify Compliance we wrote about additional actions which have been considered by the US Department of Justice to increase the pressure on companies and management. This might serve as the first step to better deal with situations where companies and management deliberately put patient safety at risk.

from the net……………..