Drugs and the pharmaceutical sciences

Filter Manufacture Quality Assurance and Validation 359
Raw materials supplied to the vendor are checked first to determine whether the
quality documentation is complete. Again, depending on the criticality of the component,
the material might undergo specific tests to verify that the quality standards described are
met. For example, polymer granulates undergo thermal profiles to check that the quality
and type are the same as specified by the vendor to the sub-vendor. Granulates which are
used for pharmaceutical purpose also undergo specific tests like endotoxin, particulate,
and extractable tests. In other instances, the raw material is visually inspected; for
example, stainless steel tubing in regard to surface finished, damages, flaws, and material
stamps.
If the raw material does not meet just one of the specifications, the material will not
be released into production. All raw material batch records are kept with the batch records
of the resulting product. The product has to be completely traceable to allow appropriate
investigation, if necessary. Raw material suppliers are generally audited once a year,
depending on the significance of the raw material supplied. However, if there has been an
incident the supplier will be audited immediately thereafter and corrective action verified.
At that point the audit frequency could also increase until the reliability level required by
the manufacturer is achieved.
For example filter cartridges, whether pre- or membrane filter, are tested for
extractables (Fig. 4) to check whether there is any change within the profile, which might
not meet release criteria (Jornitz and Meltzer, 2001; Meltzer and Jornitz, 1998). Similar
tests are flow, throughput, mechanical and thermal robustness. Membrane filters are
commonly individually integrity tested before release.
Stainless steel products also have specific definitions, which need to meet the
biopharmaceutical requirements (Jornitz and Meltzer, 2001). These are individual
stamping of the steel goods, welding certification, material qualification, and
certification. The steel source can determine the quality of the steel. The steel
Identified Extractables Filter Cartridges from Several Filter Manufacturers
Cartridge A Cartridge B Cartridge C Cartridge D Cartridge E* Cartridge F* Cartridge G* Cartridge H*
Dietyhlphthalate Cyclohexan Propionic acid Dietyhlphthalate Acrylic acid Dimethylbenzen Etherthioether Caprolactame
Stearic acid Ethoxybenzoic
acid
Diphenylether 12 oligo. aliphates 2 phenolic oligo. Etherthioether Propionic acid
Butyrolactone
2,6-Di-tert.-butylcresol2,6-Di-tert.-butyl2,6-Di-tert.-butylcresolcresol
Hydroxybenzoic
acid
2,6-Di-tert.-butylcresol2,6-Di-tert.-butylcresol
2,6-Di-tert.-butyl-cresol Laurinlactame
2,2-Methylene-bis Cyclohexadiene 4-Methyl-2,5- Tert.-butyl-methyl- 3 oligo. Benzyl-di-
4-ethyl-6-tert. Buty 1,4-dion cyclohexediene-1 2,5-cyclohexadiene phenylmethan
phenol
on
1-on
3,5-Di-tert. butyl-4hydroxyphenyl
propionate
3,5-Di-tert.-butyl-methyl- Laurinlactame derivate
2,5-cyclo-hexadiene-1-on
Hydroxybenzoic
acid
Phenylisocyana Hydroxybenzoic
acid
2,4-Bis(1,1-dimethoxy-1-ethyl)phenol
Triphenylphosphite 2 N-containing high
MW compounds
4,4-Dichlorodiphenylsulfone4-Methoxy-4-chlordiphenylsulfone
7 oligo. Siloxanes Palmitic acid Palmitic acid Succinic acid Stearic acid Acetamide
Benzothiszolone Adipinic acid
Bis-(2-ethylhexyl)phthalate
Stearic acid Dimethox/dipheny 3 oligo, siloxanes
sulfone
Bis-(2-ethylhexyl)phthalate
N-cont. aromatic high 4-Hydroxypropyl-benzoat
MW comp.
Dibutylphthalate
12 oligo. Aliphates 12 oligo.
aliphates
11 oligo. aliphates Polyether
Polyacrylate 3 oligo. amides 6 oligo. Aliphates Ethylhexylphthalate
4-Methyl-2,5cyclohexadiene-1on
11 oligo.
siloxanes
Methoxy-4-chiorodiphenylsulfone
Ethylacrylate Bis-(2-ethylhexyl)phthalate
Hydroxyphenyl acetamide Dihydroethyl-phthalate
Methyl-4hydroxybenzosBis-(2-ethylhexyl)phthalate
Diphenylphthalate 10 oligo. siloxanes Methoxy-4-chlorodiphenylsulfone
2,6-Di-tert.-butyl-cresole
Etherthioether Polyether
9 oligo. Siloxanes 2 oligo. aliphates 7 oligo. Siloxanes Disobutylphthalate
7 oligo. sioxanes
6 oligo. aliphates
Cyclohexanone
Diacetylbenzene
2,4-Bis(1,1-dimethoxy-1-ethyl)phenol
Cyclotridecanone
4-4-Dichlorodi-phenylsulfone
Propionic acid
4 oligo. siloxanes
3 oligo. aliphates
*Identification of the RP-HPLC peaks by FTIR is still in progress—extractables list of marked cartridges may be incomplete.
FIGURE 4 Table of extractables of eight different sterilizing grade filters.