Docket Management
Docket: 00D-1418 - Q7a ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Comment Number: ECT-5

Accepted - Volume 1

Comment Record
Commentor Mr. CHRISTOPHER DOBSON Date/Time 2000-10-20 00:00:00
Organization Glaxo Wellcome
Category API/Dosage Manufacturers

Recommended Changes / Reasons
Lines: 623-627
Section: 6.71
Change the text for the whole of 6.71 (lines 623 to 627) to: Batch production and laboratory control records for the manufacture of the API from its intermediates should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records for earlier stages may be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s). Any deviation from critical process steps or parameters for any stage should be reported to the quality unit(s) and an investigation performed. Material affected by deviations should not be released for further processing or distribution without the authority of the quality unit(s).
Recommended Change Type: General Comments The current version of Line 128 in section 2.22 requires the quality unit to review all critical steps. This is restated in the current version of 6.71 lines 623 to 627. My firm believes this requirement is removing all the potential benefit associated with 6.73 lines 630 to 631 which allows the release of intermediates to be delegated to the production unit. In practice almost all registered stages contain at least one critical step and in fact many investigators identify adding the key raw materials as a critical step which happens in every stage! Aside from raw material addition, our technical department has reviewed every registered stage and indicated that poor control around one or more process steps in each intermediate stage could or would have an adverse impact on product quality. We believe that an objective assessment of registered stages by other companies would come to the same conclusion. In practice then, the current proposal would require the quality unit to review every batch record in order to check critical process steps and eliminate the main benefit of the opportunity to delegate release of intermediates to production. Within other sections of the document we believe there is an adequate level of control over critical steps and parameters. Line 130 within 2.2 places a responsibility on the quality unit to have all deviations investigated, lines 157 to 158 within 2.3 ensures production report any deviations, lines 560 to 563 within 6.5 ensures they are investigated and lines 584 to 585 that they are documented. In summary we believe the proposed amendment allows appropriate delegation to production within a framework of an exception reporting system such that any problems with critical process steps are reported, investigated and documented prior to release of the affected material. This point is of significant concern and importance to my Company.
Lines: 128-130
Section: 2.2
Change the text of 2.22 point 3 line 128 to: Reviewing completed manufacturing records for final API stages and ensuring all other manufacturing records are reviewed by qualified production personnel or other units before release of the API. Change the text of 2.22 point 4 line 130 to: Making sure that deviations from critical process steps and parameters are investigated and resolved by developing and approving an appropriate system and by the auditing of intermediate stage batch records.
Recommended Change Type: General Comments This wording is proposed to support the implementation of my first recommendation relating to section 6.71. We believe that as well as ensuring there is a system in place for reporting deviations, a regular audit of a proportion of intermediates' batch records would reinforce the system. Please note this point is of particular significance and concern to my Company.
Lines: 668-686
Section: 7.30
Change the text of 7.30 to: At least one test to verify the identity of each batch of material should be conducted unless a Supplier Approval program provides an adequate assurance. A supplier's Certificate of Analysis may be used in place of performing other tests. For materials released without an identity test, visual examination of containers, labels and recording of batch numbers should help in confirming the identity of these materials. For certain materials such as highly toxic or hazardous materials, sampling and testing may be impractical. In such cases the precautions outlined above should be taken and where necessary additional down-stream testing should be performed to confirm the addition of the correct materials. The lack of on-site testing for any of these materials should be justified and documented. 7.31 stay as is. 7.32 delete (covered by amended 7.30)
Recommended Change Type: General Comments It is traditionally accepted that omission of an identity test of hazardous or highly toxic materials is acceptable. In the current environment, Health and Safety specialists are declaring more and more materials hazardous or toxic and creating considerable debate and conflict. The interesting feature of this is that an incorrect hazardous or toxic material addition is more likely to create a quality problem than is the addition of a neutral, less reactive species. Thus if one accepts the logic of not testing hazardous materials, this principle should be extendable to all raw materials. In some circumstances identity testing will still be necessary but it is our view that knowledge of our process combined with a strong Supplier Approval program should allow identity testing to be eliminated when justified irrespective of the nature of the substance. For example if you have visited your supplier and know that material was manufactured on a dedicated plant; if you know the supplier takes his sample at the point of offload; if you have confidence in his label control system and if you have received a certificate of analysis for the material, sampling to confirm identity adds very little to the overall assurance. There are other contributing justifications which would be used on a case-by-case basis. If one considers a reaction: Intermediate A + Side Chain B = Intermediate C. Almost all output stages are now covered by an HPLC analysis for identity and purity. If either A or B is not the correct material, then one will not produce C and the material will fail control tests. This is after the fact but provides added security. Some argue that identity testing can pick up cross-contamination - it might but it would usually not. Some argue that identity testing can detect a rogue container - the statistics are against. In a delivery of 20 tonnes (400 x 50kg sacks) you would need to sample 380 sacks to have a 95% chance of detecting a rogue. In summary the industry is investing more and more into good Supplier Approval programs and it is our view that this can replace identity testing in many circumstances eliminating double-handling of materials and reducing risk to both staff and product. This would still achieve the "what" of assured identity of raw materials via a different "how" which requires considerably less material handling. We should support inclusion of the key features of an acceptable Supplier Approval programme into the document if it would facilitate inclusion of the above point. Please note this point is of particular significance and concern to my Company.
Lines: 1019-1023
Section: 11.50
11.50 ... storage conditions and retest or expiry dates... would be better as ..storage conditions and retest periods or shelf lives.... This is also applicable to line 1032 and line 1052
Recommended Change Type: General Comments A retest date or an expiry date are specific to a particular batch whereas the retest periods or shelf lives are applicable to the material and would be used to set the relevant dates for a batch. The same could be applied to lines 1045 and 1049, but it can be argued that these paragrpahs are referring to specific batches and therefore it is not necessary to change.
Lines: 505-505
Section: 6.30
..... or other identification numbe; "numbe" is missing an "r" to give "number"
Recommended Change Type: General Comments
Lines: 144-145
Section: 2.2
replace .... to support retest or expiry dates.... by ...to support retest periods or shelf lives..
Recommended Change Type: General Comments As for recommendation 4. Retest dates and expiry dates are batch specific whereas retest periods and shelf lives refer to the material.
Lines: 1301-1303
Section: 14.3
Suggested text: 14.30 Before a decision is taken to rework batches that do not conform to established standards or specifications (i.e. subject them to one or more processing steps that are different from the estbalished manufacturing process), an investigation into the resaon for non-conformance should be performed.
Recommended Change Type: General Comments Lines 1284 to 1291 effectively contain the definition of "reprocessing" whereas there is no similar definition of reworking within lines 1301 to 1303. The proposed text would aid the reader.
Lines: 1736-1736
Section: 20
Delete "Expiration Date:"
Recommended Change Type: General Comments Not part of this definition
Lines: 1739-1739
Section: 20
Replace "during" by "before"
Recommended Change Type: General Comments Text refers to a date before which material should be used not a period during which it should be used.
Lines: 58-59
Section: 1.3
API Starting Materials normally have defined chemical properties and structures and a well-defined impurity profile such that its method of manufacture does not affect the quality of the derived drug substance.
Recommended Change Type: General Comments The extra words will help to give confidence that the material truly is a starting material such that the method of manufacture is not relevant and can allow some flexibility in sourcing. Whether or not this recomendation is accepted, it is important that there is consistency between this document and the Common Technical Dossier definition of a Starting material, otherwise there will be difficulties and confusion.



ECT-5