Developing a

Cleaning Process:
Cleaning in Development
By Birgitte Holst

INTRODUCTION

The discipline of cleaning validation is as individual as process

validation, but the methods, techniques, and risks are almost identical in
all kinds of pharmaceutical manufacture. Process understanding is the
magic term when assessing what must be done and the effort to be put
into the documentation of equipment status.
A smooth technology transfer and successful cleaning validation in the
manufacturing plant can optimise time to market for a new product. Lack
of cleaning process understanding can cause expensive surprises in the
late phases of bringing products to market. It is, therefore, worthwhile to
invest development time in the cleaning process.

A number of crucial conditions are needed for optimising time to

market. Technology transfer of the cleaning process should encompass
these conditions:
1. Cleaning process impact on product residues and equipment
surfaces
2. Rationale for testing residues after cleaning in the manufacturing
plant
3. Test and analytical method validation for testing residues in the
manufacturing plant
4. Cycle development of the cleaning process in the manufacturing
plant
[Make sure the process is able to clean the equipment with relevant
product residues before cleaning validation begins.]

4 Institute of Validation Technology

 Birgitte Holst

Technology transfer of the cleaning process does not encompass any

focus on the microbial condition in the equipment after cleaning, because
this parameter is not scalable. The risk this implies to the patient and the
product should rule the challenge and monitoring of this parameter in the
individual equipment setup - in the pilot facility as well as in the manufac-
turing facility.
The primary scope of this article is to establish timely cleaning process
understanding and a perspective for the use of this knowledge during
manufacturing clinical trials. The intention is to present important general
aspects for handling cleaning processes in development when preparing
for technology transfer (Part I) as well as when manufacturing for clinical
trials (Part II).
Included with the general aspects some specific examples for perform-
ing risk assessment are stated. The examples included are from the
authors daily experience with cleaning validation in Novo Nordisk A/S, a
company manufacturing biotechnology active pharmaceutical ingredients
(API) as well as related parenteral finished pharmaceuticals.

PART I
DEVELOPMENT OF A CLEANING PROCESS
Timeliness
What is timely process understanding and timely development of
a cleaning process?
Understanding of a cleaning process should be documented as part of
the development report. Set aside time for the development of the cleaning
process as product development progresses.
Cleaning process understanding can imply almost as many preparing
for Good Manufacturing Practice (GMP) disciplines as traditional develop-
ment of drug product processes or API processes require, but the time
spent is a minimal fraction when invested at the right moment. When
developing a cleaning process, the process should be as effective, as
safe, as environmentally sound, and as cost-efficient, as possible.
The technology transfer of a product to the manufacturing plant should
encompass a cleaning process designed for manufacture: a robust and
scalable cleaning process.
The cleaning process in the manufacturing plant must support expecta-
tions from authorities as indicated in Reference 1: Food and Drug
Administration (FDA) Draft Guidance from 2005, Amended New Drug
Applications (ANDA) - Impurities in Drug Products:

Cleaning Validation 5
Birgitte Holst

We recommend that ANDA sponsors develop robust

formulations and manufacturing processes that are based
on sound state-of-the-art scientific and engineering princi-
ples and knowledge. Although routine manufacturing varia-
tions are expected, significant variation in batch-to-batch
impurity levels or an unusually high level of impurity may
indicate that the manufacturing process of the drug
substance is not adequately controlled or designed.

Costly time in the manufacturing facility can be wasted if a mistake in

design of equipment or cleaning process occurs because of a lack of
understanding. Gathering know-how before the technology transfer can
help to foresee some of the difficulties the manufacturing facility might face
when scaling-up the cleaning processes.

Gathering Know-how
What kind of know-how is needed and what effort does it require?
You do not have to spend a lot of extra time and resources when
gathering know-how about the cleaning process, just remember to relate
the gained results from product development (e.g., regarding degradation,
stability, etc.) to the production and cleaning process residues in the
equipment.
Know-how and process understanding of the cleaning process
includes knowledge about:
Level of toxicity and potency (basis for establishment of Maximum
Allowed Carry-over (MACO)) and cleanability (basis for worst-case
evaluations) of :
Product residues
Degradation of products generated in the time lapse to cleaning
Degradation of products generated in the cleaning process
Impact on stability from carry-over of product residues, cleaning
agent, and degradation products (basis for establishment of
MACO)
Level of toxicity of the cleaning agent and residues from the
cleaning agent after the cleaning process (basis for establishment
of MACO)
Rationale for the:
Functionality and optimal concentration of the cleaning agent
Cleaning process sequences (e.g.: pre-rinse, alkaline wash,
rinse, acidic wash, rinse, drying)

6 Institute of Validation Technology

 Birgitte Holst

Cleaning process parameters (time, temperature, time lapse

from use to cleaning)
Compatibility of the agent with different types of surface materials

Know-how and process understanding in development can come from:

Experiments (preliminary studies in discovery, process
development studies, process challenge studies)
Experience and data obtained from test and toxicology productions
Experience and data obtained from similar processes
(e.g.: existing processes)
Scientific rationales

Can we, in advance, scientifically justify application of a cleaning

process when we do not have the final equipment for testing?
Yes, if we base the scientific justification for applying the same cleaning
process to different products on similarities from product to product,
compare residues from different products in the rationale, and discuss
similarities in characteristics. In addition, laboratory tests can justify
similarities or differences in cleanability.

When introducing a new product in an existing manufacturing

plant, can we reduce the cleaning validation effort by performing
laboratory tests?
Yes, if former cleaning validation studies can be nominated as
worst-case scenarios and cover cleaning validation studies for the new
product partly or totally, when scientific justification for a better cleanability
is present.
If any doubt is present, verify the theory in practice by performing a
confirmation study at final scale at essential, hardest to clean areas. Let
the risk that the cleaning process applies to the next product rule the
scope of the confirmation study.
Remember that impact from differences in the process time and time
lapses prior to cleaning can change the cleaning scenario and necessitate
a nomination of a new worst-case scenario. This situation should lead
to new validation studies despite the scientific justification for better
cleanability of the different products in the small scale studies.
Perform cleanability studies, e.g., as laboratory tests, but consider pros
and cons when choosing the laboratory test method. Justify and document
the use and limitations of the test.

Cleaning Validation 7
Birgitte Holst

Methods for cleanability comparison:

Solubility in relevant solvents
Simulated clean-in-place 2 (CIP)
Dip test performed with stainless steel
sintered tablets 3:
Dip in cleaning solvent with controlled stirring
Analyse tablets by weighing before and after dipping and drying
Using radioactive marked material
Other tests

Use only well characterised laboratory tests with documented

reproducibility when tests are used to compare different scenarios and
limit final scale studies.

PART II
CLEANING PERSPECTIVE FOR
CLINICAL TRIALS MANUFACTURE
In this section, some of the scientific rationales related to the tasks in
cleaning validation will be handled in the context of the effort needed for
documenting a clean surface in a pilot facility.
Once all the equipment in a pilot facility is qualified, the author has
found that the majority of the effort for defining a cleaning validation
should be performed at the desk, because it is important that everything
we do, or choose not to do, is justified with scientific rationales. These
rationales must be present prior to performing any test or study that will be
used to document the status for the equipment.
We seldom have identical plants with identical production schedules;
therefore, the arguing and risk assessment should be documented in an
individual cleaning rationale for the specific product and pilot facility in
question. Most of the arguments and risk assessment possibilities dis-
cussed below can enter into a cleaning validation rationale for a manufac-
turing plant as well as for a pilot facility.

Qualification of the Equipment a Precondition

To ensure consistency of an automated cleaning process, the state of

8 Institute of Validation Technology

 Birgitte Holst

control for a qualified cleaning process should be kept by configuration con-

trol and appropriate surveillance of cleaning process parameters: Time,
Action, Concentration, and Temperature (TACT).

Validation in Pilot Facilities

Must a cleaning process in a pilot facility be validated?
As with all other questions regarding validation, the answer is: It
depends! It depends upon the manufacturing situation. For example, is
reproducibility of the cleaning process to be used or needed in the manu-
facturing context?

Could means other than validation contribute to the safety of the

patients receiving the clinical trial product?
Yes, verification or monitoring from time to time can be an option, too.
The definitions are as noted in Figure 1.

Figure 1
Definitions

Term Definition

Cleaning Documented verification that the cleaning process, can perform

Validation effectively and reproducibly, based on the approved cleaning
method and cleaning acceptance criteria.
A confirmation by examination and provision of objective evidence
Cleaning that specified cleaning requirements have been fulfilled.
Verification Verification studies must be planned and documented in the same
manner as validation studies.
Documented routine examination performed as a process control
Cleaning based on approved cleaning acceptance criteria.
Monitoring Monitoring studies are usually planned in standard operating
procedures (SOP) and documented as part of the batch record.

To do nothing is not an option because the cleaning process has the

possibility to contribute to the API and/or the drug product with impurities
not originated from the production process. These impurities are
oftentimes contamination beyond product specification. Contamination
beyond product specification must always be minimized to a well-defined
and acceptable level whether generated by the cleaning process or by
residues from the former production process.
Verification and monitoring may provide the insurance needed for
avoiding risk to the product and patient, but how to decide what to do
will be discussed in the next sections.

Cleaning Validation 9
Birgitte Holst

Why is control of residues after a cleaning process needed in

preclinical and early clinical studies, when it is a fact that APIs in
these studies have a high level of impurities, impurities originated
from the production process?
Because impurities originated from sources other than the production
process or the product itself are regarded as contaminants and can blur
the preclinical and clinical results.4
Taken to its logical conclusion, residues can be toxic, and must be
questioned as needed. In other words, the contribution to the impurity
profile for the next batch or the next product depends on the scenario for
what is going on in the equipment before or while the cleaning process is
performed prior to production of the next batch or the next product.

The Regulatory Frame

Interpretation of regulatory requirements can answer some of the tricky
questions.

Do authorities expect us to perform cleaning validation or verifi-

cation in a pilot facility?
Yes they do.

The regulatory frame for cleaning is as follows:

API: [Reference 5] - ICH Q7A, EU GMP Part II
Drug products: [Reference 6] - EU GMP Annex 13

The International Conference on Harmonization (ICH) Q7A and the

European Union (EU) GMP Part II say: During all phases of clinical
development, equipment should be clean and suitable for its intended
use.

EU GMP Annex 13 says:

In clinical trials there may be added risk to participating

subjects compared to patients treated with marketed
products. The application of GMP to the manufacture of
investigational medicinal products is intended to ensure
that trial subjects are not placed at risk, and that the results
of clinical trials are unaffected by inadequate safety, quality,
or efficacy arising from unsatisfactory manufacture. Equally,
it is intended to ensure that there is consistency between
batches of the same investigational medicinal product used

10 Institute of Validation Technology

 Birgitte Holst

in the same or different clinical trials, and that changes

during the development of an investigational medicinal
product are adequately documented and justified.

The toxicity, potency, and sensitising potential may not

be fully understood for investigational medicinal products
and this reinforces the need to minimise all risks of
cross-contamination. The design of equipment and
premises, inspection or test methods and acceptance
limits to be used after cleaning should reflect the nature
of these risks. Consideration should be given to campaign
working where appropriate. Account should be taken of
the solubility of the product in decisions about the choice
of cleaning solvent.

The requirements are interpreted this way:

A scientifically sound rationale must give an account of the risk
for carry-over to both the next batch in a campaign and the next
product when bringing a new product into a pilot facility.
When there is a risk to the patient or the product, we must document
that the risk is minimised to an acceptable level by cleaning valida-
tion, verification, or monitoring. The context will rule what to do.

A Changing Environment
Cleaning processes and documentation of the equipments cleaning
status is a greater challenge in a pilot facility than in a manufacturing facility
because new products or changed products are introduced all the time.
Developing means that changes can happen from the production of
one batch to the production of the next batch of the same product. Such a
scenario can lead to a change in product residues before cleaning and the
carry-over of different residues in a campaign as illustrated in Figure 2.
In most phases, performing cleaning validation in process development
will not be appropriate because changes in the production process can
result in changes of residues.
As partly indicated in Figure 2, it is a fact that a cleaning process gen-
erates different impurities dependent upon the product residues, the actual
equipment, and the use patterns for the actual equipment.

The simple illustrations in Figures 3 and 4 show examples of other

implications for the changing environments in development.
The initial production processes for preclinical and clinical batches might

Cleaning Validation 11
Birgitte Holst

not generate identical impurities and all relevant impurities might not have
been part of the preclinical batches (no toxicology study has implied the
impurities). That is one more very good reason for testing the cleaning
status of the equipment with validated test and analytical methods prior to
production of a clinical batch production. The test and analytical methods
must be validated in relation to the content in the equipment prior to the
cleaning process.
The challenge is to relate existing validated processes and methods to
new situations. The new situation might compromise the validated state of
the processes and methods. A sound and scientific cleaning rationale for
the new or changed product must account for whether or not the validated
state rules or a new or modified approach must be used.

Cleaning Rationale for a New Product in the Pilot Facility

The scientifically sound rationale must take into account the risk of
bringing a new product into a pilot facility. Three types of carry-over are in
question:
Carry-over to the next batch in a campaign
Carry-over to downstream processes if equipment is shared
Carry-over to the product when product change-over occurs

Accounting for the risk implies a scientific discussion about:

How risk from some residues can be regarded as mitigated
How accept limits for what is left will be established
How compliance to accept limits will be documented

Figure 2
Residue Carry-over: Changes in residues can provide changes in
carry-over despite manufacturing the same product in development

Residues
from
B

12 Institute of Validation Technology

 Birgitte Holst

Figure 3
Illustration of a Scenario that Provides One Matrix of Carry-over to
Product B

Figure 4
Illustration of a Scenario Providing another Matrix of Carry-over
to Product B

Figure 5
Batch-to-batch Contamination Can Occur in a Campaign

Residues Residues
after after
clean clean

Equipment Equipment Clean

Production Cleaning Clean Production Cleaning Production
ready for ready for equipment
mode process equipment mode process mode
cleaning cleaning

Figure 6
Downstream Contamination Is Possible when Equipment Is Shared

A in Residues Residues A in Residues Residues A in

process from after process from after process
A A clean B B clean A

Equipment Equipment Clean

Production Cleaning Clean Production Cleaning Production
ready for ready for equipment
mode process equipment mode process mode
cleaning cleaning

Cleaning Validation 13
Birgitte Holst

Figure 6
Downstream Contamination Is Possible when Equipment Is Shared

A in Residues Residues A in Residues Residues A in

process from after process from after process
A A clean B B clean A

Equipment Equipment Clean

Production Cleaning Clean Production Cleaning Production
ready for ready for equipment
mode process equipment mode process mode
cleaning cleaning

Carry-over to the Next Batch in a Campaign

A pilot facility often manufactures in campaigns, a kind of dedication.
Carry-over of residues to the next batch in a campaign does not have
the same perspective as carry-over to the next product and the only
concern should be that the batch receives acceptable limits of:
Degradation products
Residues from the cleaning process

If the product is a final dosage form, you must, in addition, look at the
impact of the strength of the product.

Scenarios in a campaign
If the product is produced in a campaign with no changes in the
campaign that can affect the residues as indicated in Figure 5 and
Figure 6, perform appropriate verification and monitoring docu-
menting that batch-to-batch contamination is acceptable.

If the campaign is long, the verification and monitoring studies

can be collected with a conclusion as though it were a validation
study.
Afterward, no verification need be performed because the
validated state for cleaning between batches has been
established.

If the product is produced in a campaign and changes as indicated

in Figure 2 take place, perform appropriate concurrent verification
and monitoring and document that batch-to-batch contamination is
acceptable all through the campaign.

14 Institute of Validation Technology

 Birgitte Holst

Figure 7
Next Product Contamination after Change-over

Product Residues Residues Product B

A from after cleaning with residues
A process from A

When producing as in either scenario one or two, verification should

document that the equipment is clean before change-over to alternative
production can take place. The scope of this study might be quite different
from the study that documents no risk for batch-to-batch carry-over.

Carry-over to Downstream Processes when Equipment Is Shared

A batch can receive carry-over from the upstream process when two or
more steps in a production process are performed in the same equipment.
This scenario is illustrated in Figure 6.

Carry-over to the Product when Product Change-over Occurs

Contamination of next product, illustrated in Figure 7, can come from
three sources:
Residues from a former production process
Degradation products from a former production process
Residues from the cleaning process

Scenarios for change-over

Compared to contamination in a campaign, a simpler picture can be
drawn when having a product change-over, but the risk is usually higher to
the patient and the product. A higher risk should elicit a greater effort
when documenting the cleaning status of the equipment. If the product
comes into the equipment only once, verification should document that the
equipment is clean before change-over so alternative production can take
place.

Cleaning Validation 15
Birgitte Holst

How Risk from Some Residues Can Be Regarded as Mitigated

Could residues from different products be compared and justifica-
tion found for applying the same cleaning process to different
products without applying full blown cleaning validation or
cleaning verification?
Yes, but be careful and scientific. Process knowledge and understand-
ing are the key words. Use experience from former studies when prepar-
ing the rationales prior to entering a new product in the equipment and the
associated facility. The approach to be used is founded on what usually is
referred to as the matrix approach, product grouping or bracketing, in a
manufacturing multi-purpose plant.

The new product should be defined with regard to the following attributes:
Composition
Solubility
Cleanability
Treatment regime
Potency
Toxicology
Allergenicity (e.g.: mammalian host cell proteins)

If the new product, compared to products already manufactured and

tested in the facility, can be regarded as less challenging in each of the
above mentioned groups, but the last, the rationale can state that already
performed cleaning validation is representative for the new product. This
cannot be done for allergenicity. When there is a risk of generating levels
of concern of allergenic compounds, special attention must be taken.

The rationale for evaluating that the initial, validated cleaning process
still applies, must also come from the use patterns of the equipment in the
production process:
Identical production processes regarding:
Process conditions: temperature, time, agitation, etc.
Mother liquor/content in the process stream
Time lapses
Possibilities or risks for upstream or downstream cross-contamination

Use a risk-based approach to evaluate the areas of risk:

Limit the cleaning verification study to these areas
Balance the scope of the study to the risk it implies
Small changes may call for a confirmation study only

16 Institute of Validation Technology

 Birgitte Holst

Appropriate monitoring should be applied, e.g.: visual clean

Residues from the Former Production Process

Cleaning process knowledge and understanding is crucial when
defining product residues from a production process. Product development
activities should have revealed, to some extent, the composition of the
product including impurities present in the product. Impurities may already
be defined with regard to potency and toxicity.
Use information from already performed degradation and stability
studies combined with toxicology studies. This information is important
knowledge for risk assessing and for establishing limits.

Almost identical processes

The former production process could be almost identical to the next
production process.
The rationale for evaluating that the initial, validated cleaning process still
applies can be established on process knowledge and understanding from:

Clarification studies performed in the laboratory regarding solubility

and ratio of cleanability of product residues
Similarities in substances, e.g.: of broth and strain of organisms,
solvents, salts, preservatives, etc.
Similarities in process steps

For example, in fermentation it can be argued that the same strain

of organism produces approximately the same impurities and, therefore,
the challenges for the cleaning process could be identical for different
products.

Inactivation
In addition, the rationale can be built on process knowledge and on
an understanding of the ability of the cleaning process to inactivate the
product residues. Again, already performed degradation studies can
provide some science to this rationale.

Degradation Products from the Former Production Process

In the interval between the production process and the cleaning
process, degradation products can be generated. The residues from the
production process can undergo changes that will render a different

Cleaning Validation 17
Birgitte Holst

cleaning scenario compared to the cleaning scenario immediately after the

production process:
Moisture will evaporate from the surface and leave residues more
fixed to the surface
Air can promote the degradation process (oxidation)
Microbial growth can promote the degradation process

The amount of degradation products can be lowered by limiting the time

lapses from use to cleaning.

Some knowledge regarding degradation products can already be

present e.g., in API recovery or purification steps, degradation products
might be similar to impurities already present in residues from the former
production process.

Degradation products = By-products

Residues from the Cleaning

Compliance must
Process
be documented by
Degradation products from
adherence to acceptance
the cleaning process and
residues from the detergent criteria derived from
should be considered. If the established MACO.
cleaning process performs Documentation for
satisfactorily by using time, compliance will then
action, and temperature only be found in trend
(TAT and not TACT), residues
reports, verification,
can be mitigated by not using
detergent. or validation reports.
By using agents that are
identical to raw materials used
in the production process (e.g., acids and alkaline solutions) limits can be
established from using knowledge about the products sensibility to these
agents (e.g.: pH challenge and justification studies). Residues from acids
and alkaline solutions can easily be tested by simple methods (pH and
conductivity).

Final Production Steps

At early steps in product manufacture for APIs, a high level of by-prod-
ucts is present and later purification steps are specifically designed to take

18 Institute of Validation Technology

 Birgitte Holst

care of these impurities. The rationale for not testing carry-over from the
cleaning process can be process knowledge and understanding.
If by-products from the production process and degradation products
from the cleaning process are shown to be identical and later purification
steps are designed and tested to remove the relevant level of impurities of
this origin, no validation or verification should be needed.
Contrary to this, special attention should be given to the final
production steps where no purification steps can remove any impurities.
The total amount of carry-over will contribute to the impurity profile of
the final products.

What if we have limitations for scientific testing?

In some situations we do not have any product that can be used for
the development of test methods for cleaning verification before the first
production has taken place.

Then, we can always reduce the risk by:

Ensuring visible cleanliness
Using the first batch after a change-over only for test and not for
clinical trials
Using a blank run with the relevant mother liquor (relevant to the
change-over batch), to ensure a homogeneous distribution of
possible residues in the liquor and analyse a sample of the liquor
for content of the previous product
Using disposable equipment where leachables are eliminated as a
potential risk
Handling the equipment in dedicated cleaning cycles
Placing the used equipment in quarantine until the clean status can
be documented with validated methods

A Forced Ranking tool for systematically evaluating the risk and

decision-making is provided in the Appendix.[See Reference 7 and
Acknowledgement 2.]

How Maximum Allowed Carry-over will be Established

How MACO will be established has been covered by many other
articles, but two subjects under this heading should be discussed:

How to continue when next product is unknown?

MACO and the related acceptance criteria for product A in question
must be calculated by using knowledge of the next product B.

Cleaning Validation 19
Birgitte Holst

Typically, that knowledge is not present when planning production of A,

but by using a worst-case approach for carry-over, an approximation can
be made:
Smallest batch size and lowest potency ever seen in the pilot
environment
Largest area of shared surface

When the next product B is known, check that the data match the
worst-case approach:
If the new worst-case scenario is not present you are home safe
If the new worst-case scenario is present you must show a lower
carry-over of the previous product A

How will compliance to MACO be documented?

We can document conformance to specifications for cleaning by clean-
ing validation, cleaning verification, or cleaning monitoring. Which to use
should be discussed and scientifically justified in the rationale.

Documents
Compliance must be documented by adherence to acceptance criteria
derived from established MACO. How to comply must be planned either in
SOPs, verification, or validation protocols. Documentation for compliance
will then be found in trend reports, verification, or validation reports. If
verification studies are done three or more times, the verifications studies
might be presented with a conclusion as though it were a validation study.
Thereafter, the validated state for cleaning prior to change-over to next
product is in place and no further studies are needed.

Controlling the validated state

Being in the validated state must appear from planning and controlling
the campaign e.g.: in SOPs and in process control records.

20 Institute of Validation Technology

 Birgitte Holst

CONCLUSION
Cleaning validation might apply in a pilot facility, but if the risk
assessment shows that cleaning validation studies in a campaign do not
provide higher quality to the product and cleaning validation only raises
the development costs, cleaning validation should not be done.
Validation of a cleaning process toward a specific product in a pilot
facility can be of limited value because the production process changes
concurrently with the development phases, other means, such as cleaning
verification and monitoring, may be sufficient. When change-over to next
product occurs, means other than cleaning validation can show that risk
to patient and product quality has been mitigated by a well performed
cleaning process.
The effort for control of a new product in a plant must be looked upon
in context of former assessments and former cleaning activities. Gather
know-how and reuse already gathered know-how. If a proper effort for the
cleaning process is invested in development, it can speed up the time to
market. In addition, an effort for gathering cleaning process understanding
in development is in-line with Process Analytical Technologies (PAT)
thinking.
Cleaning processes will continue to be a challenge with the same
velocity as the industry invents new products.

REFERENCES
1. FDA draft guidance, 2005: ANDAs: Impurities in Drug Products
2. Alfredo Canhoto, Ph.D. Wyeth BioPharma. A Novel Bench Scale Apparatus to Model
and Develop Biopharmaceutical Cleaning Procedures. Journal of Validation Technology,
Vol. 11, Nov. 2004.
3. Borer Chemie are using the method as part of proactive R&D of cleaning agents to cus-
tomers. http://www.borer.ch
4. ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological /
Biological Products
5. ICH Q7A identical to EU GMP Part II: Basic Requirements for Active Substances used
as Starting Materials
6. EU GMP Annex 13: Manufacture of Investigational Medicinal Products
7. Rebecca Brewer, Dober Group, 1-800-323-4983, rbrewer@dober-group.com

Cleaning Validation 21
Birgitte Holst

ACKNOWLEDGEMENTS

1. Great thanks to my patient husband and banker, Henrik Rong, former

novice in cleaning, but in theory no more, he made the article readable
for English-speaking readers.

2. The author extends great thanks to Rebecca Brewer for an always

inspired approach to cleaning validation. [See reference number 7.]

ABOUT THE AUTHOR

Birgitte Holst has worked for Novo Nordisk for more than 20 years,
always with validation as a theme. Ms. Holsts main experience has been
gathered in the manufacture of aseptic products and biotech APIs.
Currently, she holds the position as manager for a corporate expert
team in validation that is serving as internal consultants. Ms. Holst holds
a M.Sc. in Pharmacy from The Danish University of Pharmaceutical
Science. She may be reached by telephone at +45 4444 8888 / + 45
3075 8019 or by email at: bho@novonordisk.com.

Originally published in the April 2006 issue of the Journal of GXP Compliance

22 Institute of Validation Technology