Wednesday, 28 December 2016

Analytical Methods: Validate or Qualify?

The terms 'validate' and 'qualify' are both applied to analytical methods, often leading to confusion, so which is the correct term to use? If you consult the dictionary definitions of each word you could probably successfully argue that either of the terms could be applied to the process of demonstrating that a laboratory test method works as it is supposed to. Therefore what we really need is a consistent terminology whereby everyone understands the same thing when these terms are used.

In my experience, there is already quite good agreement but confusion can arise from the slightly different approaches that are taken for test methods for small pharmaceutical molecules compared to large biopharmaceutical molecules. If you have always worked with small molecules, then it is quite likely that you have never applied the term 'qualify' to an analytical test method and are much more likely to apply it to a laboratory instrument. However, in large molecule testing laboratories it is fairly common to 'qualify' methods in early stages of development and 'validate' them in late stage development.

Often, although not always, these early stage methods for large molecules can be quite generic, and they may be referred to as 'platform' methods. At this stage it is not claimed that the test method is completely optimised for the molecule of interest in the expected sample matrix and so when demonstrating its fitness for purpose, the term 'qualify' is felt to be more appropriate.

This is similar to the principle applied in instrument qualification where we are not claiming that all test methods will work on the instrument but that the instrument is fit for use. I think that the approach in computer system validation, as described in the EU GMP Annex 11, is helpful: "The application should be validated; IT infrastructure should be qualified." You can think of the analytical test method like a specifically set up piece of software and an instrument like an operating system. So qualification is for general (supporting) situations and validation is for specific ones.

Whether you agree with the approach of using both terms for analytical test methods depending on the stage of development, or you prefer to always use 'validate' for test methods because 'fit for purpose' covers all stages of development (both approaches seem to be accepted by regulatory authorities), it is still useful to know how the use of the terms has evolved in the pharmaceutical/biopharmaceutical industry so that any confusion can be removed.


 

Friday, 16 December 2016

Problems Storing HPLC Water?

HPLC Troubleshooting Tips from MTS
The use of water in HPLC mobile phases can be a source of many problems. In this blog post we look at the effects of storage and how to prevent storage related problems.

When you make up fresh mobile phase you probably assign an expiry date based on the fact that you know the solvent mixture will be subject to change over time but what you may not consider is the storage of the solvents prior to mobile phase preparation.

In the case of water, this can have significant detrimental effects on your chromatography. The primary reason is that water is a great solvent. It can absorb contaminants via leaching from the container in which it is stored, and it can also absorb contaminants, such as airborne bacteria, from exposure to the atmosphere. These contaminants are likely to increase the total organic carbon (TOC) in the water which in turn can lead to chromatographic problems such as: noisy and drifting baselines; extra (unexpected) peaks, often referred to as 'ghost' peaks, and in extreme cases problems with retention times and peak shapes.

The extent and impact of these effects will depend on the nature of the HPLC method that you are using. For some methods you may not see any detrimental effects and for others it can be absolutely critical. Contaminants are much more likely to show up, and thus create problems, if you are using UV detection at low wavelengths, in the area of  ~ 210nm, or sensitive mass spectrometry. In these cases it would be worth investigating the effects of water storage and source (e.g., lab purification system vs. bought in bottled water) as part of robustness in method development so that the problem and issues are understood fully before the method is in routine use.

To prevent these problems (or reduce them as much as possible) the following is advised:
    HPLC Troubleshooting Tips from MTS
  • Don't store water, get it fresh before use.
  • Discard the first 1-2 litres from the water purification system.
  • Use glass containers for water.
  • Don't attach plastic tubing to the delivery point of your water purification system.
  • Look after your water purification system, maintain it well and don't ignore warning lights!
  • For critical methods, investigate the effect of water storage (and source) as part of method development.

 

Thursday, 15 December 2016

Validation & Transfer of Methods for Biopharmaceutical Analysis

We have decided to split our popular course, 'Validation & Transfer of Methods for Pharmaceutical Analysis', into two versions: one for traditional small molecules - 'Pharmaceutical Analysis'; and another for large molecules - 'Biopharmaceutical Analysis'. Although the content of the two versions will be very similar, this approach will allow use of case studies, scenarios and examples which are tailored to the needs of the learners.

The dates for both versions of the course may be found on the course list page of the MTS website.

 

Wednesday, 14 December 2016

25% Discount on Books

We are offering a 25% discount on our books, 'Validation of Analytical Methods for Pharmaceutical Analysis' and 'An Introduction to HPLC for Pharmaceutical Analysis', as a special end of 2016/beginning of 2017 offer.
Just £22 each (plus shipping if applicable).
Offer ends 31st January 2017.
Visit the MTS website to buy your copies today.


 

Tuesday, 13 December 2016

Course Dates for 2017

MTS Ltd Training Course Calendar for 2017
The MTS course calendar for 2017 is now available. Click here to view the calendar and visit the course list page on the MTS website for more information on all the available courses.

 

Thursday, 17 November 2016

MTS Recommends... Application of QbD and QRM to Analytical Method Validation

W. Saffell-Clemmer and J. Karty, "Application of QbD and QRM to Analytical Method Validation,"
Pharmaceutical Technology 40 (11) (November 2016).

"To further understanding of QbD concepts to analytical method development and validation, the tools suggested in the Stimuli article were combined with the guidance in ICH Q2(R1) for this case study, and applied to the validation of a stability-indicating high-performance liquid chromatography (HPLC) method for Protopam drug substance (Baxter) and Protopam chloride for injection meeting ICH Q3A(R2) and ICH Q3B(R2) standards for impurities."

Thursday, 3 November 2016

HPLC Training Courses in Dublin, 6th to 9th February 2017

We are running our series of HPLC courses in Dublin in February 2017.  Aimed at all would-be HPLC users, troubleshooters and method developers. 

The courses are as follows:

How to Run HPLC Methods: Monday 6th February 2017
Ideal for anyone new to HPLC, this course will demystify all the parameters required to run a HPLC method.

How to Troubleshoot HPLC: Tuesday 7th February 2017
Will suit HPLC users who want to be able to keep their HPLC system up and running, by sorting out problems as they occur.

How to Develop HPLCMethods – Part 1: Wednesday 8th February 2017 & How to Develop HPLC Methods– Part 2: Thursday 9th February 2017
These two courses can be taken together or separately and will describe a strategy for selecting the best HPLC method conditions for your separation.

We are offering the following discounts until 9th January 2017:
€350 per person per day, 2 days for €650, 3 days for €950
or 4 days for €1250
Academic discounts and group discounts also available up to 9th January, contact us for a quote.
After 9th January all courses are charged at full price of €425 per person per day.

Includes:
  • Comprehensive handouts for each course containing useful reference data.
  • Free tools to help you use HPLC efficiently.
  • A Certificate of Attendance. There is an optional post training assessment to obtain a Certificate of Training.
  • Expert Advice from the MTS trainer on your HPLC problems, both on the day of the training and after the event.
 

Monday, 17 October 2016

MTS Recommends... Paper, Paper Everywhere but None of it Controlled?

Paper, Paper Everywhere but None of it Controlled?

By Chris Burgess, Bob McDowall
LCGC Europe, Sep 01, 2016, Volume 29, Issue 9, pg 498–504

"One of the common threads in the six data integrity guidance documents published to date is the need to control any blank forms used in regulated GXP laboratories. This month’s “Questions of Quality” is focused on how to interpret the regulator’s requirements for this topic. We also pose the question: Is paper the best way to record regulated data?"

Thursday, 18 August 2016

Data Integrity: New guidance now available on EMA’s website

The European Medicines Agency (EMA) has released new good manufacturing practice (GMP) guidance to ensure the integrity of data that are generated in the process of testing, manufacturing, packaging, distribution and monitoring of medicines.

The guidance consists of 23 questions and answers which cover a range of topics within data integrity, including aspects of the data lifecycle and associated risks, and a table which provides the link between each ALCOA principle and the existing EU GMP published in Eudralex Chapter 4 (this may be very useful for auditors new to data integrity).

Friday, 17 June 2016

MTS Recommends... Make Data Integrity Integral to CGMP Training

Make Data Integrity Integral to CGMP Training (click here to read article)

S. Schniepp, "Make Data Integrity Integral to CGMP Training," Pharmaceutical Technology 40 (6) 2016

Monday, 23 May 2016

MTS Recommends... Significant Revisions and Updates to the European Pharmacopoeia

Significant Revisions and Updates to the European Pharmacopoeia
By Susanne Keitel
Pharmaceutical Technology, Volume 40, Issue 5, pg 20–21, May 02, 2016

Tuesday, 3 May 2016

New Data Integrity Guidance from FDA

Click here to view the New Draft GuidanceFDA published a new draft Guidance for Industry in April 2016 entitled, 'Data Integrity and Compliance with CGMP', the purpose of which is to clarify the role of data integrity in CGMP for drugs and the agency's current thinking on the creation and handling of data in accordance with CGMP requirements.

The document takes the form of a series of questions and answers on data integrity issues, it is assumed that these are representative of the questions commonly asked of FDA. These include several questions which were previously posted as Level 2 guidance on the FDA website (now removed) on the topics of: paper versus electronic records; shared login accounts; and use of actual samples for 'trial' injections.

I particularly like the use of the terms 'static' and 'dynamic' (previously used in the guidance: MHRA GMP Data Integrity Definitions and Guidance of Industry March 2015) to differentiate between the different types of electronic records obtained from laboratory instruments. It is a big improvement on the previous explanation of why paper printouts were not always a viable substitute for electronic records.


MTS offers a range of services related to data integrity, click here to find out more.

 

Monday, 2 May 2016

Help on: How Much Forced Degradation?

Click here to see more MTS Helpdesk
MTS HELPDESK
Do you have any problems relating to analytical chemistry for pharmaceuticals or training? Send your questions to the MTS helpdesk using our contact form.

Question:
When I forcibly degrade my drug or drug product to create degradation products, how much degradation should I aim for?

Answer:
The aim of a forced degradation study is to generate degradation products from a drug which are both realistic and representative, typically for the purposes of assessing degradation pathways, or to create suitable samples that will allow the development of a suitable analytical method which can be used to assess the stability of the drug throughout its shelf-life.

If too little degradation occurs then it is difficult to evaluate what might happen in real time and to develop a method which can reliably determine the amount of the degradation products which could occur.

If too much degradation occurs then there is a risk that important degradation products may be further degraded and unimportant degradation products, which would not occur on storage, may be formed.

Find out more about forced degradation studies on the MTS course, 'How to Develop Stability Indicating HPLC Methods'The generally accepted industry norm for the optimal amount of degradation is between 5 and 20%, typically aiming for around  10%. Anecdotally, there is a suggestion that the 10% corresponds to the usual specification for a drug product in the US of 90 to 110% label claim.

These numbers are not quoted in regulatory guidance with the exception of the guidance from Brazil (ANVISA Resolution RDC-53/2015) which directs that results must have > 10% degradation per condition and results that are < 10% degradation, after reasonable attempt, must have scientific justification.

Find out more about forced degradation studies on the MTS course, 'How to Develop Stability Indicating HPLC Methods', click here for more information.


 

Thursday, 28 April 2016

Upcoming Method Development Course

2nd & 3rd June 2016, Hilton Garden Inn London Heathrow, UK
Early booking rate (until 5th May): £925 + VAT (20%)
Group discounts are available on request

This course is suitable for both investigating whether an existing HPLC method is stability indicating or for developing a new stability indicating HPLC method.

You will learn:
  • Why stability indicating methods are required;
  • How HPLC method parameters, such as column and mobile phase, affect the chromatographic separation and how to find the best conditions;
  • How to perform forced degradation stress studies to obtain potential degradation products; and
  • How to investigate mass balance for analytical methods.
Visit the MTS website for more information and for the online booking form.

Other related courses from Mourne Training Services:
Validation and Transfer of Methods for Pharmaceutical Analysis
Laboratory Data Integrity


 

Wednesday, 20 April 2016

MTS Recommends...

Impact from the Recent Issuance of ANVISA Resolution RDC-53/2015 on Pharmaceutical Small Molecule Forced Degradation Study Requirements

By Peter Tattersall, Suwimon Asawasiripong, Ivone Takenaka, and John A. Castoro
American Pharmaceutical Review, March 31, 2016

Friday, 15 April 2016

Data Integrity Services from MTS Ltd

Data Integrity Services from Mourne Training Services Ltd
In recent years data integrity has become a 'buzz' term in the pharmaceutical industry due to the regularity of problems being given the label during regulatory inspections. Mourne Training Services Ltd (MTS) has significant expertise in this area since integrity of data is the primary aim of all the services we offer.

MTS offers specific Training, Auditing and Consulting services relating to data integrity.

Training 
Courses in data integrity may be required to achieve a number of different outcomes such as:
  • Demonstrate commitment to data integrity in the laboratory;
  • Raise awareness for all staff to understand the issues surrounding laboratory data integrity and how it affects them;
  • Strengthen laboratory quality management systems to improve data integrity and remove falsification potential
MTS has worked with customers to design training that met these outcomes, which was customised to their unique requirements in terms of content and timings. We can do the same for you. We have designed 3 x 1 day courses that we offer as open-enrolment training which also provide a good starting point for selecting content in a bespoke course intended for in-house use.
The courses are:

1: Introduction to Laboratory Data Integrity; cGMP in the Pharma Lab
Introduces the fundamental concepts of laboratory data integrity in the context of working within a quality management system and as such this course also acts as an introduction/refresher to laboratory cGMP.

2: Applying Data Integrity in the Laboratory; Minimising Analytical Error
Deals with the effects of analytical errors on laboratory data integrity. This involves building an understanding of the nature and sources of analytical errors so that their effects can be minimised during testing, leading to high standards of data integrity and reduced numbers of OOS/OOE results due to laboratory errors.

3: How to Improve Data Integrity in the Pharma Lab
Focusses on improving laboratory data integrity and associated quality management systems by review of laboratory processes to identify data integrity risk, and implementation of appropriate solutions, paying particular attention to deficiencies that are commonly cited by regulatory authorities.

Full course descriptions are available on the MTS website.

Auditing
Data Integrity Services from Mourne Training Services LtdMTS specialises in laboratory-based audits which are carried out by myself, Oona McPolin, an IRCA certified lead auditor with extensive experience in auditing laboratories against:
  • Regulatory expectations, using standards such as the GMPs from the EU, FDA, etc.;
  • Best Practice in the analytical laboratory;
  • Specific objective requested by the customer, e.g., data integrity related issue such as audit trails.
MTS will provide an audit to suit your requirements which includes a detailed audit report and optional action plan. If a training need is indicated by the audit we can help to design and/or deliver a suitable training programme.

Consulting
MTS can assist with carrying out a gap analysis for data integrity or to provide any other assistance that you may require.

Contact us today to discuss your Training, Auditing and Consulting requirements and for a no obligation quotation.



 

Thursday, 14 April 2016

MTS Recommends... Understanding the Layers of a Laboratory Data Integrity Model

Understanding the Layers of a Laboratory Data Integrity Model

By R.D. McDowall
Spectroscopy,  Apr 01, 2016, Volume 31, Issue 4, pg 14–23

Update to MTS Company Details

Mourne Training Services is now a limited company, registered in Northern Ireland under company number NI637196.

Thursday, 7 April 2016

MTS Recommends... Understanding Measurement Uncertainty in Weighing

Understanding Measurement Uncertainty in Weighing
A scientific approach to calibration and routine testing of balances ensures accurate results.

By Ian Ciesniewski, Joanne Ratcliff, PhD
Pharmaceutical Technology, Volume 40, Issue 4, pg 78–82, Apr 02, 2016

Wednesday, 16 March 2016

MTS Recommends... Measurement Uncertainty without the Math


Measurement Uncertainty without the Math
By Chris Burgess, Pharmaceutical Technology, Volume 40, Issue 2, pg 36–40, Feb 02, 2016

Wednesday, 20 January 2016

Upcoming Course from MTS

3rd & 4th March 2016, GLS Campus Berlin, Germany
Early booking rate (until 3rd February): €1155 + VAT (19%)
Group discounts are available on request

This course is suitable for both investigating whether an existing HPLC method is stability indicating or for developing a new stability indicating HPLC method.

You will learn:
  • Why stability indicating methods are required;
  • How HPLC method parameters, such as column and mobile phase, affect the chromatographic separation and how to find the best conditions;
  • How to perform forced degradation stress studies to obtain potential degradation products; and
  • How to investigate mass balance for analytical methods.
Visit the MTS website for more information and for the online booking form.

Other related courses from Mourne Training Services:
Validation and Transfer of Methods for Pharmaceutical Analysis
Laboratory Data Integrity

 

Friday, 15 January 2016

MTS Recommends... Out-of-Trend Identification and Removal in Stability Modelling and Regression Analysis

Out-of-Trend Identification and Removal in Stability Modelling and Regression Analysis
"This article defines the concept, justification, and method of removal of out-of-trend points in stability modelling and shelf-life prediction."
By Thomas A. Little, PhD
BioPharm International, Jan 01, 2016, Volume 29, Issue 1

Tuesday, 12 January 2016

Help on: Is 'Mass Balance' Critical?

MTS HELPDESK
Do you have any problems relating to analytical chemistry for pharmaceuticals or training? Send your questions to the MTS helpdesk using our contact form.

Question:
What is the 'mass balance' for an analytical method and is it critical that I investigate it as part of method development or method validation?

Answer:
When used in the context of an analytical method, the term 'mass balance' relates to its ability to analyse the degradation products of a drug molecule. A method is considered to have 'good' mass balance if:
  1. It can quantify the loss in amount of drug molecule due to degradation (which should result in a lower assay value),
  2. It can detect and quantify the degradation products formed during degradation of the drug molecule, and
  3. The amount of the drug lost is equal to the amount of degradation products formed.
A method which is used to analyse stability samples needs to have this ability so that it can provide information on the amount of degradation occurring during the time period of the stability programme. A definition of mass balance is provided in the glossary of the ICH Guideline Q1A (R2), Stability Testing of New Drug Substance and Products:

"Mass balance:
The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error."

Typically a chromatographic technique is used since it is necessary to separate the degradation products from the drug molecule and each other to detect and quantify them. Reversed phase HPLC is usually preferred.

It is critical to investigate the mass balance of a method if it needs to be stability indicating. To meet the commitments of ongoing stability testing these methods are required for all products. For convenience, the same methods are often used for release and stability testing.

Whether the assessment of mass balance is performed during method development or during method validation often depends on the type of drug being manufactured. If it is a novel molecule then the stability indicating ability will usually be assessed during the method development phase which will allow modification of the conditions to optimise the analysis of the degradation products.

If however, it is a generic product and the testing methods are taken from a pharmacopoeia then the stability indicating nature of the method will still need to be considered but will typically form part of the method verification study. In this case modification of the method conditions is often not an option and if the method does not have good mass balance an alternative may need to be developed. For older products, which may not have stability indicating assay and degradation products methods, you may need to re-evaluate the methods to ensure that they comply with current regulatory expectations.

In both cases a stress study will be performed to force degradation of the drug molecule under a range of different stress conditions and thus create degradation products. The mass balance of the method can then be assessed. Although the concept is simple, the practical experiments to demonstrate mass balance can be rather complex and require careful planning. The phrase in the ICH guideline: "due consideration of the margin of analytical error" is significant. An added complication is that the preferred analytical technique, HPLC with UV detection, is not ideal since the size the degradation peak may not correspond to the actual amount present.

If you would like to know more about the detail of the experiments required for an evaluation of mass balance then you may be interested in the MTS course: How to Develop Stability Indicating HPLC Methods. This course is suitable for developing new methods or evaluating existing methods.

 

Wednesday, 6 January 2016

The MTS Contact Telephone Number has Changed

Please note that due to an office relocation the contact telephone number for Mourne Training Services has changed to:

+44 (0) 28 3083 4938

The postal address remains unchanged at present but will also be updated in the near future.

Monday, 4 January 2016

2016 MTS Course Calendar

The calendar for our 2016 open enrolment training courses is now available. Visit the Course List page on the MTS website for the dates and locations of all our courses in 2016.

There you will also find a detailed course description for each course, and links to the online booking forms where full details on the course fees can be found.