Professional Documents
Culture Documents
Whythe10 ppmCriterionShouldBeAbandoned
Whythe10 ppmCriterionShouldBeAbandoned
Figure 1: The weight of scientific justification of the three approaches of calculating the maximum safe surface
residue (MSSR) based on the 10 ppm, 1/1000 of the daily dose and permitted daily exposure (PDE) criteria.
Pharmacodynamics
Preclinical data
Clinical data
that is dependent on the amount of material. Defined as a administered to the patient. Assuming that therapeutic
concentration, the limit dose will depend on the maximum doses range from 0.1 mg to 5000 mg per day, the amount
amount of something else, in this case, on the amount of a contaminating substance corresponding to 10 ppm
of the following product (or API, the approaches vary) will span the same range of 4 logs. Using a limit of 10 ppm
VISIT US AT
Advanced aseptic packaging in
INTERPHEX 2016
New York – April 26-28 one operation cycle
Booth 3516 Reliable – Simple – Cost-Effective
bottelpack® Technology:
- Integrated clean room US-class 100 Your benefits:
- Recognized by GMP, FDA, JP … - Tamper-proof packaging
- Aseptic packaging of liquids, - Easy to open
creams, ointments … - Simple to use
- Endless container designs in PE, PP… - Shatter-proof, no splinter hazard
FIGURE COURTESY OF AUTHOR
www.rommelag.com
rommelag ag rommelag Kunststoff-Maschinen rommelag USA, Inc. rommelag Trading (Shanghai) Co., Ltd.
P.O. Box · CH-5033 Buchs, Switzerland Vertriebsgesellschaft mbH 27905 Meadow Drive, Suite 9 Room 1501 Xinyin Building
Phone: +41 62 834 55 55 · Fax: +41 62 8345500 P.O. Box 1611 · D-71306 Waiblingen, Germany Evergreen CO 80439, USA No. 888 Yishan Road · 200233 Shanghai, P.R.China
E-mail: [email protected] Phone: +49 7151 95811-0 · Fax: +49 7151 15526 Phone: +1.303. 674.8333 · Fax: +1.303.670.2666 Phone: +86 21 6432 0166 · Fax: +86 21 6432 0266
E-mail: [email protected] E-Mail: [email protected] E-mail: [email protected]
Equipment surface
Maximum daily dose PDE
Product (API) Batch size [kg] used to make the
[mg] [μg]
product [m2]
A 40 582 99 7
G 1440 216 59 10
K 450 120 99 5
without risk characterization of exposure is equivalent Can 10 ppm be used to identify risks according
to pretending that it makes no difference if a drug is to the EMA guideline on shared facilities?
contaminated by 1 ng (the equivalent of 10 ppm of 0.1 mg) The EMA guideline (2) describes primarily a method for com-
or by 50 mcg (the equivalent of 10 ppm of 5000 mg) of the puting health-based limits based on all available toxico-
same substance. logical and pharmacological information, which are termed
Whether the contaminant is Botox or a mild antacid, permitted daily exposure (PDE). The guideline’s focus is not
the limit amount computed by 10 ppm will be the same. on how to set cleaning limits. The PDEs are only one ele-
Therefore, involvement of a risk assessment scientist (e.g., ment needed to set cleaning limits, which are calculated as
toxicologist or physician) is crucial for the characterization MSSR. The other element is the knowledge of the efficiency
and differentiation of health risks and the overall risk of a cleaning process, which is independent from the next
management process. Figure 1 compares the weight of product. Therefore, while there is a link between PDEs and
scientific justification for three different approaches to cleaning limits, they are absolutely not the same. This is
compute the maximum safe surface residue (MSSR). In expressed in the EMA guideline, which says, “these levels
contrast to approaches targeting 10 ppm and 1/1000th of can be used as a risk identification tool and can also be used
the daily dose, the permitted daily exposure (PDE) approach to justify carryover limits used in cleaning validation.”
ensures that available preclinical and clinical data are An evaluation of the effect of using 10 ppm in addition to
considered in computation of the MSSR. PDE to identify risks was performed with the example of an
actual product portfolio of a multiproduct API manufacturing
Does the 10-ppm limit ensure good cleaning? facility making 11 different APIs. The basic data of the APIs
No; 10 ppm is a concentration unit that gives no indication are given in Table I.
on cleanliness. Operationally, a sensible physical unit for All changeovers from a preceding product (α) to a following
cleanliness must express the amount of residue per unit sur- product (β) were considered. The matrix of maximum
face area (e.g., mg/m2). By switching from carryover (amount safe carr yovers (MSC) was first calculated according
of residue [g]) to cleanliness [mg/m2], the surface is normal- to Equation 1. In a second step, the matrix of MSSR was
ized, and the cleanliness of all pieces of equipment of a calculated by dividing the MSC by the equipment surface
facility can be compared; cleaning results between facilities area used to make each following API (see Equation 2).
and even between companies can also be compared. When Each cell of the MSSR matrix shown in Table II reflects
speaking of cleanliness, the size of the equipment does an individual product change from an API α to an API β
not matter; “cleanliness” is an intensive property of the and contains the MSSR for the particular change (i.e., the
equipment. Therefore, until the 10 ppm has been converted cleanliness required to make the corresponding API β when
into a cleanliness value in [mg/m 2], it is not possible to say it is made after API α).
what level of cleanliness the 10 ppm eventually represent. The PDE-based matrix in Table II shows a vivid landscape
Depending on the particular situation, 10 ppm may mean with strong contrasts, with values from 5 to 146,970 mg/m2.
1 mg/m 2, which can be hard to reach, or 50 mg/m 2, which It is easy to identify the changeovers that pose the greatest
should be easy to reach. risks. Comparing the calculated MSSRs with the results of
54 Pharmaceutical Technology JANUARY 2016 P h a r mTe c h . c o m
Cleaning Limits
Table II: Matrix of maximum safe surface residue (MSSR) based on permitted daily exposure (PDE).
MSSR values < 25 mg/m2 are underlined.
Following Product:
Preceding
A B C D E F G H I J K
Product
A 193 6 43 175 133 18 278 9 8 19
B 9847 61 409 1675 1276 170 2663 84 76 180
C 29394 5528 1222 5000 3809 508 7949 251 226 539
D 12198 2294 75 2075 1581 211 3299 104 94 224
E 12198 2294 75 507 1581 211 3299 104 94 224
F 4850 912 30 202 825 84 1312 41 37 89
G 1470 276 9 61 250 190 397 13 11 27
H 48941 9204 301 2035 8325 6341 847 418 376 897
I 2205 415 14 92 375 286 38 596 17 40
J 146970 27640 904 6111 25000 19043 2542 39744 1255 2694
K 735 138 5 31 125 95 13 199 6 6
Table III: Maximum safe surface residue (MSSR) (mg/m2) required when the 10-ppm criterion is applied compared to
the lowest MSSR required by applying the permitted daily exposure (PDE). MSSR < 25 mg/m2 are underlined.
Based on: A B C D E F G H I J K
10 ppm: 59 55 18 18 25 57 37 40 9 34 12
PDE: 117.6 110.6 4.5 30.6 50.0 95.2 12.7 79.5 6.3 5.6 13.5
AIR VENT
MSC α [g] × 1000
MSSR α [mg/m2] = [Eq. 2]
Surface for β [m2] SLOPED EDGE
X
EMBOs PREVENT
“SEMI-LOCK” BEFORE and MAIN LOCK
For example, the changeover from product D to product E SEPARATION AFTER FILLING
was calculated as follows:
83 μg × 470 kg
. Non-animal based capsules
Made from hypromellose (HPMC)
MSCD =
100 [mg]
83 × 10 -6 g x 470 × 103 g
. Extremely suitable for hygroscopic/
ŵŽŝƐƚƵƌĞƐĞŶƐŝƟǀĞŵĂƚĞƌŝĂůƐĂŶĚ
= ĨŽƌŵƵůĂƟŽŶƐ
100 × 10 -3 g ůƐŽƐƵŝƚĂďůĞĨŽƌĮůůŝŶŐůŝƋƵŝĚƐ
= 390.1 g
. 'ƌĞĂƚĂůƚĞƌŶĂƟǀĞƚŽĐŽŶǀĞŶƟŽŶĂů
ĐĂƉƐƵůĞƐĨŽƌǀĂƌŝŽƵƐĐƵůƚƵƌĂů#ƌĞůŝŐŝŽƵƐ#
and dietary requirements
Kh<ŽƐŚĞƌ!/&E,ĂůĂůĞƌƟĮĞĚ
= 2075 mg/m2
Pharmaceutical Technology JANUARY 2016 55
Cleaning Limits
Five products C, G, I, J, and K are potentially at risk, but the identification and analysis of cross contamination risks.
only when they follow certain products, like A, G, I, and Moreover, it may impose more stringent limits for cleanli-
K. Similarly A, G, I, and K represent a risk for the other ness than are required by health authorities without adding
products, but not for all of them. to the patient safety. Eliminating an unnecessary require-
The comparison of the matrix of MSSR based on PDE with ment serves to focus attention and resources on high-risk
the known efficiency of the cleaning processes allows for a situations. The 10-ppm criterion offers no scientific or prac-
sound identification of risks in line with the spirit of the EMA tical benefit and can be discontinued in cleaning validation
guideline. The comparison may give the concept of “worst- practice.
case approach to cleaning validation” a new orientation by
shifting the focus from the hazards of worst-case products Acknowledgements
(with regard to solubility, cleanability, toxicity, etc.) to the The authors would like to thank Ed Sargent and Courtney M.
worst-case risks, (i.e., to the “risky” changeovers between Callis for their views during compilation of this manuscript.
two products). Such risks will have to be mitigated, for
example, by development of better cleaning procedures, References
avoiding high-risk changeovers by careful campaign 1. European Commission, The Rules Governing Medicinal Products in
scheduling and dedication of certain process lines or parts the European Union; Volume 4 EU Guidelines for Good Manufacturing
of the equipment to a group of products. It is important, Practice for Medicinal Products for Human and Veterinary Use (Brussels,
however, to accept that cleaning will have its limits: There August 2014).
will be cases where the risk cannot be mitigated by 2. EMA, Guideline on Setting Health Based Exposure Limits for Use in Risk
cleaning alone. Identification in the Manufacture of Different Medicinal Products in
How does the risk identification work with the 10-ppm Shared Facilities (London, November 2014).
rule? Because the calculation is independent of the 3. European Commission, Volume 4 Good Manufacturing Practice (GMP)
preceding products, the matrix collapses to a list of batch Guidelines, Parts I & II, http://ec.europa.eu/health/documents/eudralex/
sizes divided by 105 (see Table III). The 10-ppm-based vol-4/index_en.htm, accessed Dec. 1, 2015.
MSSRs all come out in a narrow range, between 9 and 59 4. European Commission, Volume 4: EU Guidelines for Good Manufacturing
mg/m 2 and they do not really allow clear differentiation Practice for Medicinal Products for Human and Veterinary Use, Annex 15:
between the high- and low-risk changeovers. Compared to Qualification and Validation (Brussels, February 2014).
PDE, the 10-ppm calculation does not improve the detection 5. FDA, Code of Federal Regulations, Part 211 Current Good Manufacturing
of high risks. Practice for Finished Pharmaceuticals, www.accessdata.fda.gov/scripts/
In practice, the 10-ppm methodology gives the impression cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211, accessed Dec. 1, 2015.
that there are no low-risk changeovers. If the 10-ppm row 6. Ministério Da Saúde Agência Nacional De Vigilância Sanitária, Dispõe
in Table III is followed, whenever C, D, I, or K is made, the sobre as Boas Práticas de Fabricação de Insumos Farmacêuticos Ativos
manufacturer has to meet the MSSR dictated by 10 ppm. (Brazil, December 2014).
The assumed cleaning limit of 25 mg/m 2 will not meet the 7. Agência Nacional de Vigilância Sanitária—Anvisa, Validação de limpeza
requirement to make C, D, I, or K in any case, independently para farmoquímicas, http://portal.anvisa.gov.br/wps/wcm/connect/244
of what the preceding product was. 3e9804f1af51ea138bdc88f4b6a31/Guia+de+valida%C3%A7%C3%A3o+d
The high MSSR values in Table II merely reflect the low e+limpeza+para+Farmoqu%C3%ADmicas.pdf?MOD=AJPERES, accessed
risk associated with the corresponding changeovers. They Dec. 1, 2015.
should not be read as cleaning limits. The suspicion that 8. Health Canada, Cleaning Validation Guidelines, Guide-0028 (Ontario,
production will set the cleaning limit at the level of the January 2008).
PDE-derived MSSR is not justified. Even if the MSSR values 9. South Korea, Good Manufacturing Practice for Medicinal Products for
for particular changeovers are high, this does not justify Human Use, Enforcement Regulation of Pharmaceutical Affairs Act
reducing the cleaning effort, because cleaning will still [Annex 2], http://wenku.baidu.com/view/42de6028ed630b1c59eeb53e.
have to fulfill the requirement of visually clean equipment. html, accessed Dec. 1, 2015.
This will be sufficient to ensure a suitable minimal hygiene 10. South Korea, Provisions for Conducting Validation for Drugs, etc, The
standard. KFDA Notification No. 2009-173 (December 2009)
The cleaning limit should also be based on the knowledge 11. China FDA, Good Manufacturing Practice for Drugs (2010 Revision), http://
of the c apabilit y and the reliabilit y of the cleaning eng.sfda.gov.cn/WS03/CL0768/65113.html, accessed Dec. 1, 2015.
processes, and it will ideally be set as far below the MSSR 12. FDA, Validation of Cleaning Processes (7/93), Guide to Inspections:
as reasonably possible. I nsp e c tio ns of Clea ning Pro ce s se s ( 7/93), w w w.f da.gov/ I CECI /
Inspections/InspectionGuides/ucm074922.htm, accessed Dec. 1, 2015.
Conclusion 13. PIC/S, Recommendations on Validation Master Plan, Installation and
There is no scientific justification for a limit concentration Operational Qualification, Non-Sterile Process Validation, Cleaning
that ignores the hazards presented by potential contami- Validation; PI 006-03 (September 2007).
nants. Implementation of the 10-ppm criterion in cleaning 14. G.L. Fourman and M.V. Mullen, Pharmaceutical Technology, April issue,
validation does not ensure safe cleaning. and it may distort 54-60 (1993). PT
56 Pharmaceutical Technology JANUARY 2016 P h a r mTe c h . c o m