INVOLVEMENT OF HEALTHCARE REGULATORY AFFAIR PROFESSIONAL IN OVERSEAS REGISTRATION PROCESS

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Testing: 

Atypical and Out of Specification Results:
All atypical results and all OOS results on samples stored within recommended storage conditions and shelf life must be investigated, evaluated and clearly documented, according to procedure. If an OOS result, obtained on samples stored under accelerated conditions or beyond shelf life, is expected (e.g. a low assay follows the trend established for other samples and conditions) no investigation is required, but the documentation must include a statement to acknowledge that the result has been assessed, is valid and acceptance.

Reporting Stability Results:
The results obtained from stability testing should be assessed and reported, including any decisions made. This should include an assessment of any trends or outlines observed, as well as a comparison against the end of life specification.

Reference should be made to the predicted effects of the product change(s) on the product stability, and to whether or not these effects have been seen in practice.

Notification of Stability Failures:
Failure in studies running in support of Clinical Trials should be notified within 24 hrs to the person responsible for the CTS The failure of post approval stability studies to meet specification either at end of life, or during storage, should be notified to FDA.  For studies run in support of NDAs, the FDA should be notified using the Field Alert mechanism. In European markets the relevant licensing authority should be advised of the failure. The QA and manufacturing area should be contacted also to notify them of the failure within 24 hrs and to participate in the investigation and corrective action. All  details should be documented in the relevant project of study file.  

Testing scope for DRUG SUBSTANCES
• Physical-chemical properties
– Appearance
– Water content
– pH
– Color / clarity of solution
– Thermo analytical stability
» Melting point
» Polymorphism

• Chemical properties
– Assay
– Degradation products

• Microbial properties
– (Microbial purity)

Testing scope for TABLETS
• Physical-chemical properties
– Appearance
– Mean mass
– Water content
– Hardness
– Disintegration
– Dissolution

• Chemical properties
– Assay
– Degradation products

• Microbial properties
– Microbial purity

• Container closure system properties
– Functionality tests (e.g. extraction from blister)

Testing scope for CAPSULES
• Physical-chemical properties
– Elasticity
– Mean mass
– Mean filling mass
– Water content (Capsule and content)
– Disintegration
– Dissolution

• Chemical properties
– Assay
– Degradation products

• Microbial properties
– Microbial purity

• Container closure system properties
– Functionality tests (e.g. extraction from blister)

Testing scope for oral LIQUID FORMS
• Physical-chemical properties
– pH
– Color & clarity of solution
– Loss on weight
– Viscosity
– Particle size distribution (for oral suspensions only)

• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants

• Microbial properties
– Microbial purity

• Container closure system properties
– Functionality tests

Testing scope for LIQUID FORMS for inj. and PARENTERALIA
• Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution

• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants

• Microbial properties
– Microbial purity

• Container closure system properties
– Functionality tests

Testing scope for SEMI LIQUID FORMS
• Physical-chemical properties
– Appearance, odor, homogeneity, consistency
– Loss on weight
– Viscosity
– Content uniformity (within the container)

• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants

• Microbial properties
– Microbial purity

• Container closure system properties
– Functionality tests

General requirements for COPP Application:
1.    A forwarding letter/application shall be addressed to DDC(I)/ADC(I) of respective CDSCO zonal/sub zonal  offices with copy of covering letter & product summary sheet to DCG(I) (WHO-cell) by authorized person only.
2.    The forwarding letter/application shall be accompanied with List of products applied for grant of COPP, along with the product permission copy (manufacturing licence issued by the SLA) & notarized product summary sheet, site master file as per WHO-GMP requirement.

S. No.

Name
of the
product

Number of batches produced in last two years (with scale R&D/Pilot/ Commercial)

Stability studies (maximum period completed) in months Accelerated / Real time

Process Validation

Analytical Method Validation

Cleaning Validation
/verification

Annual Product Review

If permitted
by DCGI Y/N/NA

Completed/
Not completed

Completed
/Not completed

Completed
/Not completed

Completed
/Not completed

Acc

R. T.

1

Example Tablet

20 (Commercial)

6 M

36 M

Completed

Completed

Completed

Not Completed

Y

3.    Manufacturing layout (it is preferred if men and material flow, pressure flow drawing are also given)
4.    HVAC schematics and details of areas (Where in clearly specify the filtration level & classification of core areas & rooms as required in section 3.3 of SMF) and Water system – Schematic diagrams along with the components.
5.    List of personnel (with designation, qualification & experience), List of equipments, instruments, utilities along with make and model & capacity.
6.    List of primary & secondary Impurity and Reference standards/cultures available with the firm (relevant to the applied products for grant of COPP).

Model Certificate of a Pharmaceutical Product
Certificate of a Pharmaceutical Product1

This certificate conforms to the format recommended by the World Health Organization (general instructions and explanatory notes attached).
No. of Certificate:
Exporting (certifying) country:
Importing (requesting) country:
1.    Name and dosage form of product:
1.1    Active ingredient(s)2 and amount(s) per unit dose:3
For complete qualitative composition including excipients, see attached4.
1.2    Is this product licensed to be placed on the market for use in the exporting country?5 Yes/No (key in as appropriate)
1.2    Is this product actually on the market in the exporting country? Yes/no/unknown (key in as appropriate)
If the answer to 1.2 is yes, continue with section 2A and omit section 2B.
If the answer to 1.2 is no, omit section 2A and continue with section 2B.6
2A.1    Number of product licence7 and date of issue:
2A.2    Product-licence holder (name and address):
2A.3    Status of product-licence holder:8 a/b/c (key in appropriate category as defined in note 8)
2A3.1    For categories b and c the name and address of the manufacturer producing the dosage form are: 9
2A.4    Is Summary Basis of Approval appended?10
yes/no (key in as appropriate)
2A.5    Is the attached, officially approved product information complete and consonant with the form are: 9 Yes/no/not provided (key in as appropriate)
2A.6    Applicant for certificate, if different from licence holder (name and address):12
2B.1    Applicant for certificate (name and address):
2B.2    Status of applicant: a/b/c (key in appropriate category as defined in note 8)
2B2.1    For categories b and c the name and address of the manufacturer producing the dosage form are: 9
2B.3    Why is marketing authorization lacking?
Not required/not requested/under consideration/refused (key is as appropriate)
2B.4    Remark: 13
3.    Does the certifying authority arrange for periodic inspection of the manufacturing plant in which the dosage form is produced?
Yes/no/not applicable14 (key in as appropriate If no or not applicable proceed to question 4.
3.1    Periodicity of routine inspections (years):--
3.2    Has the manufacture of this type of dosage form been inspected? Yes/no (key in as appropriate) Do the facilities and operations conform to GMP as recommended by the World Health Organization? 15 Yes/no (key in as appropriate)
4.    Does the information submitted by the applicant satisfy the certifying authority on all aspects of the manufacture of the product? 16
Yes/no (key in as appropriate)
If no, explain:
Address of certifying authority:
Telephone number: ----------------------------------
Fax number: --------------------------------------
Name of authorized person:
Signature:
Stamp and date:

General Instructions Please refer to the guidelines for full instructions on how to complete this form and information on the implementation of the Scheme. The forms are suitable for generation by computer. They should always be submitted as hard copy, with responses printed in type rather than handwritten. Additional sheets should be appended, as necessary, to accommodate remarks and explanations.

Explanatory notes
1. This certificate, which is in the format recommended by WHO, establishes the status of the pharmaceutical product and of the applicant for the certificate in the exporting country. It is for a single product only since manufacturing arrangements and approved information for different dosage forms and different strengths can wary.

2. Use, whenever possible, International Nonproprietary Name (INNs) or national nonproprietary name.

3. The formula (complete composition) of the dosage form should be given on the certificate or be appended.

4. Details of quantitative composition are preferred, but their provision is subject to the agreement of the product-licence holder.

5. When applicable, append details of any restriction applied to the safe, distribution or administration of the product that is specified in the product licence.

6. Section 2A and 2B are mutually exclusive.

7. Indicate, when applicable, if the licence is provisional, or the product has not yet been approved.

8. Specify whether the person responsible for placing the product on the market:
(a) Manufactures the dosage form;
(b) Packages and/or labels a dosage form manufactured by an independent company; or
(c) Is involved is none of the above.

9. This information can be provided only with the consent of the product-licence holder or, in the case of non-registered products, the applicant. Non-completion of this section indicates that the party concerned has not agreed to inclusion of this information. It should be noted that information concerning the site of production is part of the product licence. If the production site is changed, the licence must be updated or it will cease to be licence.

10. This refers to the document, prepared by some national regulatory authorities, that summarizes the technical basis on which the product has been licensed.

11. This refers to product information approved by the competent national regulatory authority, such as a Summary of Product Characteristics (SPC).

12. In this circumstance, permission for issuing the certificate is required from the product-licence holder. This permission must be provided to the authority by the applicant.

13. Please indicate the reason that the applicant has provided for not requesting registration:
(a) the product has been developed exclusively for the treatment of conditions-particularly tropical diseases-not endemic in the country of export;
(b) the product has been reformulated with a view to improving its stability under tropical conditions;
(c) the product has been reformulated to exclude excipients not approved for use in pharmaceutical products in the country of import;
(d) the product has been reformulated to meet a different maximum dosage limit for an active ingredient;
(e) any other reason, please specify.

14. Not applicable means that the manufacture is taking place in a country other than that issuing the Product certificate and inspection is conducted under the aegis of the country of manufacture.

15. The requirements for good practices in the manufacture and quality control of drugs referred to the Certificate are those included in the thirty-second report of the Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 823, 1992, Annex 1). Recommendations specifically applicable to biological products have been formulated by the WHO Expert Committee on biological Standardization (WHO Technical Report Series, No. 822, 1992, Annex 1).

16. This Section is to be completed when the product-licence holder or applicant conforms to status (b) or (c) as described in note 7 above. It is of particular importance when foreign contractors are involved in the manufacture of the product. In these circumstances the applicant should supply the certifying authority with information to identify the contracting parties responsible for each stage of manufacture of the finished dosage form, and the extent and nature of any controls exercised over each of these parties.

The Layout for this Model Certificate is available on WordPerfect from the Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland.

ACTD Format for Application in Asean Countries:

Permission to conduct BE Studies for Export:

Documents to be submitted for grant of permission to conduct Bioequivalence studies for export purpose.
A large number of applications are being filed to the office of DCG (I) at CDSCO (HQ) by Pharmaceutical companies, both manufacturers and importers as well as CRO’s on behalf of them,  requesting for the approval to carry out BE studies with various pharmaceutical dosage formulations  on Indian subjects.

In light of the above, for easy processing of such applications and to bring uniformity in decision making all stake holders of therefore mentioned activities are hereby advised to submit their applications with following documents. All applications should accompany the documents with proper index & page number.

Requirements for BE study of a new molecule not approved in India but approved in the other countries.

1.      Application in Form-44 duly signed, by the competent authority with name and designation.
2.      Treasury Challan of Rs. 25000/- as per Drugs & Cosmetic Rules.
3.      Undertaking by the Principal Investigator (PI) as per appendix VII of schedule “Y” of Drugs and Cosmetic Rules.
4.      A copy of the approval granted to the BE study centre by CDSCO.
5.      Sponsor’s Authorization letter duly signed by the competent authority on their letterhead.
6.      The study protocols.
7.      The study synopsis
8.      Pre-clinical single dose data and repeated dose toxicity data.
9.      Clinical study data and published report of pharmacokinetic and pharmacodynamic study carried out in healthy volunteers/patients data published in reputed journals.
10.  Regulatory status of the drug.
11.  Names of the countries where the drug is currently being marketed (to be mentioned in the covering letter also).
12.  Package literature on  the international product
13.  Complete Certificate of Analysis of same batches (both test & reference formulations) to be used in the BE study.
14.  In the case of multiple dose BE study adequate supporting safety data should be submitted.
15.  In the case of Injectable preparation the sub-acute toxicity should be submitted on the product of the sponsor, generated in two species for adequate duration.
16.  Depending on the nature of the drug like cytoxic agent, hormonal preparations etc.  Proper justification for conducting studies on healthy volunteers/patients or male/ female should be submitted.

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