pharmaceuticals export promotion council of...
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PHARMACEUTICALS EXPORT PROMOTION COUNCIL OF INDIA(Setup by Ministry of Commerce & Industry, Govt. of India)----------------------------- --------------------------------
Lr.Ref: PxIjDG/2012-13/DCGI/ dt. 28th January, 2012.
Dr GN Singh,Drug Controller General of India,Central Drugs Standard Control Organization,Directorate General of Health Services,Ministry of Health and Family Welfare,Government of India, New Delhi
Sub: EU Directive - draft guidelines - comments from our member companies
Dear Dr G.N.Singh,
We express our sincere thanks for prompt action on EU directive and development ofdraft guidelines received on 14.1.2013. We have circulated the same to our membersimmediately on 15.1.2013. We have received comments from Pharmexcil's members onsome of the points and we are herewith submitting for your perusal and for consideration.
On examination of the draft guidelines' and after taking into account the comments sent byour members, we are submitting the major points as given below:
1. In the age of Information Technology, submitting/ collecting voluminous data onphysical format is a difficult task both for submitter and receiver. It is advisable tohave the collected data in a form retrievable and useful for both. The requirementsof check list, indicate that total documentation carried by the pharma manufacturers!exporters as per GMP norms are required to be submitted for written confirmationcertificate. However, as per WHO GMP Guidelines, only SMF not exceeding 24 pagesonly is to be submitted. We therefore suggest that the check list may be simplified
) such that exporters can approach the DCGI with as little documentation as possibleand entire datal documents to be made available at the time of inspection withoutdelays/ reservations. This would ensure speedy submissions and approvals.
2. The points identified in the check list may be indicated to the applicant to make themavailable at the time of inspection for verification as most of them are confidential innature. Generation of electronic inspection reports may be advocated for betteroperational purpose as well as for easy communication in DCGI office from DrugsInspector level to DCGllevel. This will facilitate easy traceability ofthe reports.
3. we suggest that an expert committee may be constituted in DCGI office withrepresentatives of DOC, DOP , pharmacopoeia committee and Pharmexcil to guideand review the implementation of this very sensitive and critical task, as it hassignificant bearing on performance of Indian Pharma exports where DoC has targetedto achieve 25 Bn $ by march 2014.
Regd. / Head Office:101, Aditya Trade Center.
Ameerpet, Hyderabad - 500 038.Ph: 91-40·23735462/66
Fax: 91-4027375464E·mail: inlo@pharmexciLcom
Regional Office· Mumbai :lV Industrial Estate, UnH No. 211, 2nd Aoor. 248·
A S.K. Ahire Marg, Worli, Mumbai - 400 030.Ph: 91-22-24938750/51/58/59
Fax: 91-22-24938822E-mail: romumbai@pharmexciLcom
Regional Office - New Delhi:305, Padma Tower II, 22, Rajendra Palace,
New Delhi -110 008.Ph: 91-11-41536654/45062550
Fax: 91-11-41536658E-mail: rodelhi@pharmexciLcom
Branch Office - Ahmedabad:7·C, Trade Centre, Near Sladium Cross Road,
Navarangpura. Ahmedabad - 380 009.Ph: 91-79-40050497
E·mail: [email protected]
Website: www.pharmexcil.com
"
4. Proactive measures may be taken to overcome the last minutes rush and not to sufferexports due to lack of following procedures by issuing the written confirmations onpredefined conditions
S. Inorder to save time, to begin with, pending plant inspections, writtenn confirmationsmay be issued to the applicants for a limited validity, based on valid approvals held bycompanies from USFDA/ MHRA/ EDQM / CoPP etc as already agreed by EU
6. The details of Written confirmation certificates issued to Indian Pharma exporters may bekept in the CDSCOweb site for ready reference.
7, Consolidated list of comments received from our members is given under.
8, Pharmexcil is ready to undertake any activity to promote pharmaceutical exports and weare looking forward for your guidance and cooperation
9. Sir, we are also organising an interactive session with members on 4th Feb at Mumbai todiscuss this subject. We would be greatful if you can participate or depute concerned seniorofficers also to participate in the meeting.
Thanking you,
Yours Sincerely
r''''~~~-.Dr. PVAppaji, M.Pharm, Ph.DDirector General
)
End: as above
COMMENTS OF PHARMEXCIL'S MEMBERS
Checklist for documents to be submitted for application of "Written Confirmation" for activesubstances exported to the EU for medicinal products for human use, In accordance withArticle 46(2)(b) of Directives No. 2001/83/EC
I. SI.No. 1 & 2:
)
1. Covering Letter - The covering letter is an important part of the application
and should clearly specify the intent of the application (whether the
application is being submitted for the first time, whether the application is for
re-issue or is for the additional products to an existing Written Confirmation)
the list of documents that are being submitted (Index with page no's) as well
as any other important and relevant information may be provided in the
covering letter. The covering letter should be duly signed and stamped by the
authorized signatory, indicating the name & designation of the authorized
signatory alongwith the name and address of the firm.
2. An Authorization letter in original issued by the Director/Company
Secretary/Partner of the firm revealing the name & designation of the person
authorized to sign (along with the name and address of the firm) on behalf of
the firm should be submitted at the time of submission of the application
Duly self attested photocopies of the Authorization letter may be submitted
at the time of submission of subsequent applications.)
COMMENTS FROM MEMBER COMPANIES:
COMPANY-I
a. The address & contact person of DCGI as well as the Zonal/Sub-zonal
offices of CDSCO where the application should be submitted should be
provided prior to finalizing the guidelines.
b. Clarity is needed if documents are to be submitted in paper or CD-ROM or
both.
c. We recommend that one application per manufacturing site should be
submitted and the application should list all APls that are to be exported
to the E.U. from that site.
d. It is important that we are able to start submitting our applications as
soon as possible. This should be clarified in the final guidelines.
e. General :Any information, including the application itself and documents
shared with the CDSCOare highly confidential and therefore should be
)provided "confidential treatment".
COMPANY-II
Covering letter to be simplified indicating only the intent of submission. Otherinformation requested in the covering letter to be included in separateapplication form with the appropriate space for filling the details.
For points No. 5.2.8, to 5.2.25 option to be available to issue a declarationthat the documents will be available at site for review.
5.2.26 NSQ reports to be included in the list:
Confirmation statement to be issued by the CDSCOregarding maintaining theconfidentiality of the documents submitted.
)In case of surveillance audit, scope to be included to conduct desktop auditbased on the documents provided; any additional document required can berequested to avoid physical inspection.
SI.No. 3 to 8:
3. Copy of GMP certificate issued as per WHO GMP, USFDA, EDQM, etc. if any
4. Copy of Manufacturing License issued by SLA
5. List of all APls approved by SLA.
6. List of Products applied for issue of "Written Confirmation" for active
substances exported to the EU for medicinal products for human use, in
accordance with Article 46(2)(b) of Directives No. 2001/83/EC
7. List of SOPs and STPs
8. Master Formula Record and batch Manufacturing Record
COMMENTS FROM MEMBER COMPANIES:
a. Route of synthesis and process flow chart should be adequate for submissionalong with the application as the manufacturing records are available at theplant for review during the inspection.
SI.No. 9 to 17
9. Summary of Stability data (3 batches) Accelerated/ Real time (as prescribed)
10. List of Equipment and Instruments
11. List of Technical staff, their qualification, experience and their approval by
SLA.
)12. Manufacturing Layout Plan as approved by SLA
13. Validation Master Plan
14. Summary of Process validation data for 3 batches of each product.
15. Schematic Diagram of Water System specifying circulation loop and MOC.
16. Schematic Diagram of HVAC System specifying terminal filter configuration
17. Export data of last 3 years
COMMENTS FROM MEMBER COMPANIES:
a. 'Export data for the past 3 years' should not be required as it is not relevantto the GMP status of the facility and it constitutes highly sensitive businessconfidential data.
) SI. No. 18 to 20:
18. Good Distribution Practices followed by the firm.
19. Summary of Annual Product review.
20. Summary of Market Complaint Review
COMMENTS FROM MEMBER COMPANIES:
19. a. A summary of annual product review is adequate for submission along withthe application as all the details pertaining to above points are available at theplant for review during the inspection.
SI.No. 21 to 25:
21. Summary data of Impurity profiling
22. Summary data of OVI
23. Summary data of Analytical Method Validation
24. Schematic Diagram of ETP
25. Site Master File (as specified under WHO TRS823)
a. Annexure -3 requires submission of MPCR with application letter. MPCRs are highlyconfidential documents and should not be mandated to be submitted with application form.MPCRs can be audited during inspection.
20.a. Summary of Market complaint review should not be mandated to be submittedwith application form. The same can be reviewed during the inspection.
19.a. Summary of Annual Product review should not be mandated to be submitted withapplication form. The same can be reviewed during the inspection.
21.a. Summary of Impurity Profiling not be mandated to be submitted with applicationform. The same can be reviewed during the inspection.
22.a. Summary of OVI should not be mandated to be submitted with application form.The same can be reviewed during the inspection.
23.a. Summary of Analytical method validation should not be mandated to be submittedwith application form. The same can be reviewed during the inspection.
16.a. Point # 16 should be revised from HVAC to Air handling systems adopted bymanufacturer as EU guidelines does not mandate HVAC systems for Drug substances.
24.a. Point # 24 Diagram of ETPis not required in application, it can be reviewed on siteinspection.
Annexure III
I. ANNEXURE -1 UNDER EP-INS-001 :
a. On the format of the "written confirmation", right below the paragraphstarting "Regarding" the term "Categories" should be deleted
b. The written confirmation should include the "date of the last Inspection ofthe site" and the term of the "validity of the written confirmation" (i.e., 3years).
c. Once the written confirmation is provided and prior to its expiry, the timelinefor submitting a renewal application should be provided. Ideally, this should
be 1 year prior to expiration so that there is no delay in issuing a new writtenconfirmation.
d. If a facility has been recently inspected and approved by a Regulatory Agencywithin [3 months] from the date on which an application is made to obtain a"written confirmation", the CDSCO/DCGI should waive the requirement foranother inspection prior to granting the "written confirmation" as permittedby EU authorized (Q&A No.)
d.l As per the European Commission, Q&A, Version 2.0 on Importation ofActive Substances for Medicinal Products for Human Use, dated October 26,2012, Questions 18A & 18B, CDSCO/DCGIshould issue a written confirmationif a firm is inspected by an international regulatory agency such as the EURegulatory Agency or USFDA, or based on a site's existing valid WHO GMPcertificate.
d.2 Based on the documents submitted, decision to be taken for conducting the inspection;Criteria to be defined for exemption of inspection;
The proposed inspection to issue the "Written Confirmation" can be exempted if thefollowing documents are available;
1) Availability of valid COPP (for product to be exported to EU) which wasgranted by after Joint inspection carried out by CLAA & SLA.
. 2) Valid EU GMP certificate issued by competent authority of EU for the productmanufactured in the proposed site
3) Availability of valid GMP certificate/ alternate documents which can beconsidered as proof of GMP in line with EU requirements for the product withrespect to the manufacturing site. Examples: GMP certificate issued by TGA/EDQM/ Health Canada/ PMDA-Japan/ USFDA.
)d.3. Based on the Question and Answers dated 26/10/2012 issued by the European agency.Considering Q & A No. 18a and 18b;
The conditions for exemption of inspection or issuing of written confirmation based onavailable proof of CGMP compliance in line with EU requirements:
COMMENTS FROM MEMBER COMPANIES:
Procedure EP-INS-OOl includes to submit GMP certificates from WHO, USFDA,EDQM ..etc. An option of waiver of inspection should exists if the same APImanufacturing site has recently been inspected (Duration can be specified (3 -6months)) by the competent authority. This would reduce the timellne from3months to 1-2 months. The procedure as indicated is minimally 3 months. butwe hardly can imagine that DCGI will have inspectors enough to do immediately
for all API facilities an inspection. So there will be a queue. So we request to havea transition period in which API manufacturers who have sent in the applicationbut did not get an inspection still would be able to receive the writtenconfirmation.
Due consideration for recent inspections carried out by competent authorities(US-FDA, TGA-Australia, TPD-Canada, EDQM- EU, WHO and COPP inspection etc.)should be given. The recent inspection reports can be reviewed and consideredas base for CDSCOinspection agenda.
13. b. Document perse, summary of APRs, validation master plan, GDP details,process validation documents are asked. These documents are generallyreviewed on site. An open part of API DMFs should suffice for initial applicationreview before inspection.
d. 4 We would like to request you consider issuing "written confirmation" for thosesites that are in possession of a valid EU GMP so that this will help in cutting down the timerequired for getting a written confirmation. The written confirmation issuance can befollowed up by an inspection any time depending on the availability of inspectors toschedule the inspection. We propose this based on the fact that all the EU inspections aretaken up with respect to GMP guidance in ICH Q7 and EU GMP guidance
29.a. d.S Point # 29.2 and 29.3 is applicable to Medicinal products not for Drugsubstances. Adverse drug reactions are to be recorded by Medicinal product manufacturers.
16.b. Point # 35 should be revised from HVAC to Air handling systems adopted bymanufacturer as EU guidelines does not mandate HVAC systems for Drug substances.
IV FORMAT No. QA-GNL-OOIIFOI-OO
COMMENTS FROM MEMBER COMPANIES:
a. The 90-day time frame outlined in the draft guidelines should be significantlyreduced in order to ensure that all manufacturers are provided with thewritten confirmation well in advance of the deadline to minimize anydisruption to business. The reduction in the 90-day time frame should beavailable even if the recommendations noted above and supported by theEuropean Commission's Q&A are not implemented.
b. A process and timeline should be established for the review of any"observations" made during the CDSCOinitiated inspection which need to beresponded to prior to the issuing of the written confirmation.
c. A timeline should also be provided for conducting any follow-on CDSCOinitiated inspections if it is required prior to issuing a written confirmation.
To clarify the timeline for issue of "Written confirmation" after acceptance of audit responseto not more than 30 days
B. FORMAT No. EP-INS-006:
a. Any communication to the E.U. concerning the applicant's site should be firstcommunicated to the applicant and the applicant should be provided anopportunity to review the same with the CDSCOand provide any comments.In addition, applicants should be given time to respond to any observationsbefore they are shared with E.U. by the CDSCO.
b. If the observations are minor and general recommendations (based onappropriate response from the company) the report should clearly state thestatus and provide recommendation to DCGI to issue the "Writtenconfirmation" should be indicated.
)If the observations are major or critical; the report to be submitted to the company and thecompany should provide the response within a specified timeline. Based on the suitability ofthe response the audit team to decide for re-inspection or recommendation to be made toDCGIto issue the "Written confirmation".
If the re-inspection still results in the observation to be critical or major, then the non-compliance to be forwarded to EU.
Critical and major non-compliance observed after the response on the initialreport to be forwarded to EU.
c. Do we understand correctly, as per procedure EP-INS-004, point 5.4, all complaintsneeds to be submitted to the authorities. Is this linked to Export to EU countries only. Maybe more explicit in the procedure.
) d. Also EP-INS-004, point 5.5, changes (major) needs to be submitted to the authorities.Do we follow EU change guidance for classifying the change. Procedure may also includeguidance regarding the implementation of changes vis a vis authority approval.
In case of deficiencies during an inspection some of the deficiencies need modifications tothe existing systems (in terms of facility modification, document modification) which in somecases would require time for implementation. Now if a manufacturer in its compliancereport addresses these issues and commits to implement the modifications giving specifictimelines for implementation, we request DCGI to consider these situations and issue thewritten confirmation upon receipt of Compliance report from the manufacturer committingthe implementation timeline, and then plan for a re-inspection to confirm whether thefacility has stood up to its commitments.
(OR)
In case of deficiencies during an inspection if some of the deficiencies can't beaddressed immediately, the Manufacturer can propose a Corrective Action and Preventive
Action and commit a timeline to address the deficiencies in its compliance report. In suchcases we request the DCGI to evaluate the compliance report and issue a writtenconfirmation based on the fact that a Re-inspection would be initiated if necessary / checkfor compliance during the next inspection schedule and the written confirmation may berepealed if the site does not stand up to the commitments it made in the compliance report.
IV. A. DCGI Draft SOP#EP-INS-004:
1. Point: 5.2.6.4 : should be revised from HVAC to Air handling systems adopted bymanufacturer as EU guidelines does not mandate HVAC systems for Drug substances.
2. Point # 5.5 :Any changes made with respect to submitted drug master file are informedto respective regulatory authority as per their guidelines. These changes need not beinformed to local authority and should not trigger an inspection as these will anyhow becovered under next inspection as part of internal change control already there.
)1. Point # 5.2 : Only critical non compliances should be forwarded to EU.
Also we request clarity on below point:
• Will audits conducted for issue of Written confirmation involve submission of fees bythe manufacturer, if yes will the fees be applicable also for Inspection for Changes also.What will be the fee structure.
V.Typographical Corrections
, )
Please correct the "Good Manufacturing Practice (GMP) Guide forActive Pharmaceutical Ingredients ICH Harmonized TriplicateGuideline stated as per ICH Q9" to "Good Manufacturing Practice(GMP) Guide for Active Pharmaceutical Ingredients ICH HarmonizedTripartite Guideline as per ICH Q7" in all the places of the SOPswherever it is appearing.
- Please correct the typo error for the abbreviation of DOC from DeputyDirector Controlled to Deputy Drug Controller.
- In SOP number, EP-INS-003, the abbreviation for MFR to be correctedas Master Formula Record instead of Manufacturing Formula Record.
- In SOP number, EP-INS-006, under product related information, pleasedelete the words, Veterinary and IMP as the Written ConfirmationCertificate is applicable only for Medicinal Products for Human use.
To correct typographic errors under point No. 5.2.2 ICH Harmonised TriplicateGuideline as per ICH Q9 to be modified to ICH Harmonised Tripartite Guideline asper ICH Q7.