Memos - Page 6 of 15 - Cleaning Validation Simplified

2016

Should 10 PPM be Used for Limits?

A recent publication (“Cleaning Limits – Why the 10-ppm Criterion Should be Abandoned”, by Michel Crevoisier et al, PharmTech, Volume 40, Issue 1, pp 52-56) advocated abandoning the 10-ppm criterion for pharmaceutical cleaning validation limits. The authors point to the EMA document on health-based exposure limits, as well as the lack of any regulatory guidance […]

Jun

2016

Limits for Small Molecule API Synthesis – Part 3

This is a continuation of the April and May 2016 Cleaning Memos. If you haven’t read those (Part 1 and Part 2), please do so. In those previous Cleaning Memos we considered limits for intermediates, and discussed how to determine clearance of residues by subsequent processing steps. Now we’ll consider limits for cleaning of the […]

May

2016

Limits for Small Molecule API Synthesis – Part 2

This is a continuation of the March 2016 Cleaning Memo. If you haven’t read that one (Part1), it would be prudent to do so. In that previous Cleaning Memo we discussed a situation where there were two API synthesis routes for two final APIs, and these were made on the same equipment train comprised of […]

Apr

2016

Limits for Small Molecule API Synthesis – Part 1

There have been past publications on setting limits for cleaning validation for manufacture of small molecule API’s by an organic synthesis route (including the 2014 APIC guidance and some of my older publications). In my mind, none of them fully address all the complex issues involved in setting limits for these situations, which involve setting […]

Mar

2016

Meeting EMA Requirements for Existing Products

An industry working group has published a paper (A. Teasdale et al, “EMA Guideline on Setting Health-based Exposure Limits”, BioPharm International, 29:1, January 2016; also published in Pharmaceutical Technology, 40:1, December 2015) proposing a streamlined way to prioritize meeting the EMA requirement for limits in shared facilities for existing products. The EMA date for compliance […]

Feb

2016

Understanding Sources of Variation in Validation Protocols

This is a follow-up to the January Cleaning Memo where we discussed variations in cleaning processes. This month we’ll cover variations in the cleaning validation protocol itself (variation in the protocol as well as in the execution of the protocol). Reducing variability involves first understanding the sources of variation in a protocol, and then designing […]

Jan

2016

Understanding Sources of Variation in Cleaning Processes

More and more as I present training classes I am emphasizing the issue of understanding sources of variation in a cleaning process. For me, the 2011 FDA process validation guidance has been one source of this emphasis. However, it should have been more obvious to me earlier. In its discussion of 2004 pharmaceutical manufacturing in […]

Dec

2015

Special Cases in Determining “Visually Clean”

It is well known that there are a lot of variables in determining whether a surface is visually clean or not. Those variables include lighting, distance, surface roughness, angle of viewing, residue sheen, residue color, operator eyesight, and the contrast between the residue and the surface. This Cleaning Memo will focus on the last issue […]

Nov

2015

Only Read This If Applicable

Well, you are reading this, so you must have thought it was applicable. My question to you is “How did you know it was applicable?” Unless I give you more information as to the content, you cannot decide whether it is applicable or not. That information might be something like “Only read this if you […]

Oct

2015

Comparing Swab and Rinse Results

In the past, I have written (see Cleaning Memo of September 2005) that as a general rule, I expect it more difficult to get passing results with swab sampling as compared to rinse sampling. My rationale had been that when one does swab sampling, one selects worst case locations, those most difficult to clean, for […]

Sep

2015

Duration Specific Health-based Limit Values

Last month we covered “route specific” ADE/PDE values as a possible basis for cleaning validation limits. This month we will cover the issue of duration of exposure for setting ADE/PDE values. In other words, if the product containing a carryover residue was to be only administered for a short time (not a life time), is […]

Aug

2015

Route Specific Health-based Limit Values

Can ADE and/or PDE values for cleaning validation purposes be determined and used for a specific route of administration based on the possibility of residues only being transferred to a specific limited class of products (such as solid oral drug products)? The answer could be “Yes”, based on sound scientific principles. If my facility is […]

Jul

2015

Significance of GRAS

GRAS stands for “Generally Recognized As Safe”. In a recent internet forum, there were questions and statements about applying the concept of GRAS to cleaning agent residues for cleaning validation. The general tenor of questions and comments were whether GRAS status of a cleaning agent or cleaning agent component affected how limits were set. There […]

Jun

2015

What’s in Annex 15

The finalized version of Annex 15 of the EU Guidelines on GMP was released on March 30, 2015. It is a significant change from previous versions of Annex 15, at least from the prospective of cleaning validation. The previous version (2005) was merely a condensed version of key concepts in PIC/S PI 006-3. This new […]

May

2015

EMA on Limits for Shared Facilities – Part 3

This is the third in a series of Cleaning Memos discussing the finalized version of EMA’s “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”. It discusses still more additional specific issues in the November 2014 finalized version. Data Gaps for Reproductive […]

Apr

2015

EMA on Limits for Shared Facilities – Part 2

This is the second in series of Cleaning Memos discussing the finalized version of EMA’s “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”. It discusses additional specific issues in the November 2014 finalized version. TTC One issue relates to a change […]

Mar

2015

EMA on Limits for Shared Facilities – Part 1

This is the first in series of Cleaning Memos discussing the finalized version of EMA’s “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”. It was adopted by the Committee for Medicinal Products for Human Use (CHMP) on November 20, 2014. There […]

Feb

2015

What’s a Potent Active?

There seems to be at least two ways people in the pharmaceutical industry refer to potent actives. This is further confounded by the references to both “potent” and “highly potent” actives. This can lead to some confusion if we are not clear in how we use the terms. One use of the term refers to […]

Jan

2015

Regulatory Status of “Visually Clean Alone”

Recently there has been a lot of discussion on an internet forum about the acceptability of “visually clean alone” as an acceptance criterion. I believe this is based on the recent proposed changes to the EU’s GMP Annex 15 on “Qualification and Validation”. Section 9.2 of that proposed document reads in part: “A visual check […]

Dec

2014

Is Pre-cleaning Allowed?

Occasionally when I review regulatory documents, something jumps out at me that I had not fully thought about before. In a review of the FDA’s Human Drug CGMP Note of the second quarter 2001, I noticed the following FDA question and FDA answer: Question: “Must a firm quantify the amount of residue on equipment surfaces […]

Memos by Destin

Destin LeBlanc has been publishing memos on Cleaning Validation since 2001.

Should 10 PPM be Used for Limits?

Limits for Small Molecule API Synthesis – Part 3

Limits for Small Molecule API Synthesis – Part 2

Limits for Small Molecule API Synthesis – Part 1

Meeting EMA Requirements for Existing Products

Understanding Sources of Variation in Validation Protocols

Understanding Sources of Variation in Cleaning Processes

Special Cases in Determining “Visually Clean”

Only Read This If Applicable

Comparing Swab and Rinse Results

Duration Specific Health-based Limit Values

Route Specific Health-based Limit Values

Significance of GRAS

What’s in Annex 15

EMA on Limits for Shared Facilities – Part 3

EMA on Limits for Shared Facilities – Part 2

EMA on Limits for Shared Facilities – Part 1

What’s a Potent Active?

Regulatory Status of “Visually Clean Alone”

Is Pre-cleaning Allowed?

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