Unlike in pharmaceutical production, where residues on the surface of
equipment may be 100 % carried over to the next product, in API production
the carry-over risk is much lower for technical and chemical manufacturing
reasons. A group of experts from companies of the VFA discussed the chapter
"Cleaning Validation" of ICH Guideline Q7A "Good Manufacturing Practice
Guide for Active Pharmaceutical Ingredients", and recommends limits which
are 10 times higher than the limits in pharmaceutical production. This is
justified with suitable examples in a risk analysis.
2. Regulatory guidelines
In the last 10 years numerous guidelines and articles have been published
on the subject of cleaning validation.
In 1993 the FDA first published the "Guide to Inspections: Validation of
Cleaning Process". In 1996 the Pharmaceutical Inspection Convention (PIC)
published its guide (PH 1/96; current version: Recommendations PI 006-1
dated 3 August 2003), which provided a very detailed account of the
fundamental principles of qualification and validation and, in a special
chapter, of cleaning validation. Up until then the regulatory guidelines and
also the technical literature had been very strongly influenced by
experience from pharmaceutical production.
In 1997 therefore a "GMP for Active Pharmaceutical Ingredients" project
group consisting of experts from VFA member companies published a commentary
on the "Cleaning Validation" section of PIC Draft PH 1/96, taking account of
the special nature of API manufacture.
ICH Guideline Q7A "GMP for Active Pharmaceutical Ingredients" was the
first globally recognized guide to GMP for API to regulate, inter alia,
the manufacture of APIs in chemical production. This ICH guideline was
adopted by the European Commission as Annex 18 to the EC GMP Guide and,
since mid-2001, has formed the basis for API inspections.
It sets out concrete requirements for the validation of cleaning
procedures where carryover of materials posses the greatest risk to API
3. Establishment of limits in the pharmaceutical production
With regard to the scale of the work involved and to the prospects of a
successful cleaning validation outcome, setting an adequate limit for
allowable residues on production equipment has an important role to play.
Calculation is normally done based on known daily doses or on
toxicological data along with safety factors. An absolute criterion may be
applied as an alternative or adjunct to these.
The 1993 FDA Guideline requires, in the same way as ICH Guideline Q7A for
active pharmaceutical ingredients, that the residue limits should be
practical, achievable, verifiable and based on the minimum known
pharmacological, toxicological or physiological activity of the API.
Defined limits and ways of calculating the limit have deliberately not
In the PIC/S PI 006-01 Guidelines, however, the following statements are
made with regard to definition of limits.
Carry-over of product residues should meet defined criteria, for example
the most stringent of the following three criteria:
a) No more than 0.1% (1/1000th) of the normal therapeutic dose of
any product will appear in the maximum daily dose of the following product.
b) No more than 10 ppm of any product will appear in another product.
c) No quantity of residue should be visible on the equipment after cleaning
procedures are performed.
In the last 10 years the dose-based calculation (e.g. 1/1000th
dose) has prevailed In the manufacture of pharmaceutical products. Where
dose data are not available, an absolute value (e.g. 10 ppm) is prescribed.
For residues where dose data are not available but toxicological data are
(e.g. tensides), it is normal to perform the calculation based on the
NOEL/ADI (no effect level/acceptable daily intake) value along with a safety
4. Risk analysis for establishment of limits in API manufacture
Assuming that the aforementioned criteria (10 ppm, 1/1000th
dose, NOEL/ADI with SF 100) represent the state of the art for
pharmaceutical production and are considered sufficiently safety, then the
calculation of limits in API manufacture must reflect the different methods
used in pharmaceutical production and in the chemical production of active
pharmaceutical ingredients to allow comparable risk analyses to be
In pharmaceutical production a residue remaining on the surface of
equipment after cleaning is, in the next production cycle, distributed in a
mixture of active substance and excipients if it does not remain on the
surface. In the worst case it will be 100 % transferred to the first batch
of next product.
In chemical production a 100 % carry-over of residue from the equipment
surface to the next product to be manufactured can be ruled out based on the
way the process is run and on technical considerations. The residue
remaining on the equipment surface can, during the next production cycle, be
carried over into the reaction mixture consisting of solvent and raw
materials. In most cases, however, any residue in solution will be
eliminated from the process together with the solvent, and insoluble residue
by physical separation processes (e.g. filtration), so it will not be
present in the end-product.
The final step in a multi-step chemical synthesis is selective
purification of the API (e.g. by crystallization), during which contaminants
are removed from the process and/or insoluble residues are removed by
From the original reaction mixture of educt, agent and solvent there
remains only a fraction of the original mass as API at the end of the
It is also to be noted that, during subsequent pharmaceutical production,
the API is further diluted through the excipients that are added.
Assuming that there is no intention to impose more stringent yardsticks
during API production than in pharmaceutical production but that they should
be approximately the same, the logical conclusion is that the limits in
chemical production should be set higher than in pharmaceutical production.
Based on this rationale, a factor of 10 compared to the established
pharmaceutical production limits is both plausible and, in terms of
pharmaceutical risk, acceptable.
5. Establishment of limits for chemical API production
Based on the various recommendations for pharmaceutical production and
after due consideration of the differences between pharmaceutical production
and chemical production, the following scientifically founded calculation
methods are proposed for APIs.
- In all cases the production equipment, where it can be inspected, has to
be visibly clean.
- The acceptable residue must never exceed 1000 ppm, even if this were
justifiable based on dosage or toxicological data.
Furthermore, the following procedure is recommended for establishing
- The limits in chemical production may be 10 times higher than in
5.1 Limit value calculations
The limit value calculations described below also represent a ranking
order of application.
5.1.1 Calculation based on dose data -
Where dose data are available for the previous product and the following
product, the limit based on the dose criterion is set at 100th
dose in the next product. The minimum daily dose of the previous product and
the maximum daily dose of the following product shall be used for the
calculation. This type of calculation can be applied when a final API stage
follows on directly from the final stage of another API.
5.1.2 Calculation based on toxicological data - Safety factor 10
Where not all the dose data are available for all of the products, but
toxicological data for the previous product are, the limit value is
calculated according to the usual formula (ADI value, NOEL value).
In the same way as with the dose criterion (reduction from 1/1000th
to 100th), the safety factor may also be reduced from 100 to 10.
5.1.3 Absolute criterion - 100 ppm based on the quantity of the following product
When neither dose nor toxicological data are available for the previous
product, the limit is set at 100 ppm. In other words, 100 ppm (relative to
the batch size of the following product) of a defined previous product may
remain as residue on the surface of the equipment.
5.2 Limit value calculations for the "physical processes" special case
Apparatus and equipment that is used for physical end-treatments such as
drying, mixing or milling may either be operated together with the previous
synthesis equipment or generally be used separately.
During separate physical end-treatments of APIs, there is no decrease of
contaminants like in the aforementioned chemical process.
Consequently, we recommend in this case that the calculation methods
applied should be those normally used in pharmaceutical production, i.e.
1/1000th dose, NOEL/ADI with SF 100 and 10 ppm criterion.
If, however, these pieces of equipment are directly connected to the
chemical synthesis equipment, cleaning validation must have regard to the
equipment for the entire synthetic path. In this case it is not practical to
view the physical processes separately.
Consequently, for the equipment in toto either the 1/100th
dose criterion, safety factor 10 for calculation with toxicological data, or
the absolute criterion of 100 ppm are used.
For limitation or comparability of risks it should be noted that, in the
(last step) physical processes of API manufacture, the pieces of equipment
that are used may contain a maximum of 10 % of the permitted residue for the
equipment in toto. Thus, when handling the finished API, virtually the
values from pharmaceutical production are adopted.
6. Example of a risk assessment of product residues in pharmaceutical
production and in chemical API production:
Example (absolute criterion 10 ppm, simplified)