The European Union (EU) has reformed the rules for importing into the EU active substances for medicinal products for human use. As of 2 January 2013, all imported active substances must have been manufactured in compliance with standards of good manufacturing practices (GMP) at least equivalent to the GMP of the EU. The manufacturing standards in the EU for active substances are those of the ‘International Conference for Harmonisation’ – ICH Q7.As of 2 July 2013, this compliance must be confirmed in writing by the competent authority of the exporting country. This document must also confirm that the plant where the active substance was manufactured is subject to control and enforcement of good manufacturing practices at least equivalent to that in the EU.

India had earlier appointed Central Drugs Standards Control Organization (CDSCO/ DCGI) MoH as an agency to issue certification required by EU for importing API's into Europe. (Announcement). A few months ago The Pharmaceutical Export Promotion Council of India had published documents which the CDSCO was going to use for issuing written confirmation as required by the Falsified medicines directive. The Indian regulator has now published same documents on its website.The documents are available here
( Documents Published by CDSCO).

These documents give administrative procedures to be followed by the manufacturers and the CDSCO for issuing certification. One of the document mentions that the standard for issuing written confirmation would be WHO/ ICH Q 7. However CDSCO has issued another document as GMP checklist which will be used by CDSCO to confirm whether the GMP followed by an API manufacturing plant is equivalent to EU standards (ICH Q 7 / WHO). However the document issued by CDSCO is not a standard at all but merely a checklist in the form of questions. Moreover the questions do not address all or where it addresses, address adequately following requirements compared to the ICH Q 7 / WHO standards as below:

• Scope i.e. applicability of GMP’s for different stages of API manufacturing;

• Quality Management System & Principles.

• Quality Risk Management

• Clearly defined responsibilities of Production

• Product Quality Review

• Qualification of Utilities

• Process Equipment requirements

• Computerized Systems

• Deviation Handling

• OOS Handling

• Supplier Qualification

• Poorly defined requirements for In- Process Controls

• Requirements for blending of batches

• Requirements during transportation

• Requirements for using primary reference standards

• Impurity Profiling

• Poorly defined stability studies not meeting ICH requirements

• Requirements of expiry dating

• Poorly defined cleaning validation requirements

• Poorly defined Analytical method validation requirements not meeting ICH guidelines

• Change controls

• Rejection and reuse materials

• Requirements for contract manufacturers including laboratories

Apart from the technical deficiencies in the GMP checklist and many errors elsewhere , it is surprising to see that the documents have been published as SOP's and guidance documents. The "Indian Drugs and Cosmetics Act and Rules" does not have any provision for publication of a guidance document. New requirements and changes are required to be introduced only as changes to the relevant sections of the Drugs and cosmetics act, relevant rules or appropriate schedules. Therefore these guidance documents will not become a statute or a regulation or a standard and therefore will not become a condition of manufacturing license, an enforcement tool and will therefore not have any legislative sanction and legal status.

As these documents including the GMP checklist are not a condition for a manufacturing license it is not legally correct to give a certification that " The standards of good manufacturing practice (GMP) applicable to this manufacturing plant are at least equivalent to those laid down in the EU (= GMP of WHO/ICH Q7);" as per point no 1 of the certification template. An announcement on the website of CDSCO stating that for inspection ICH Q 7 will be followed does not make it a standard. India needs to adopt the ICH Q 7 / WHO guideline as GMP standard in the Schedule M of the " Indian Drugs and Cosmetics Rules" which specifies the GMP standard to be followed by API manufacturing plants in order to give such a certification.

Similarly these documents do not specify or give any details about how regular, strict and transparent controls and specific actions for effective enforcement of good manufacturing practice will be implemented. In order to give a certification that " The manufacturing plant is subject to regular, strict and transparent controls and to the effective enforcement of good manufacturing practice, including repeated and unannounced inspections, so as to ensure a protection of public health at least equivalent to that in the EU" as per point no. 2 of the written confirmation template , the measures and requirements for regular, strict and transparent controls, effective enforcement of good manufacturing practice and unannounced inspections needs to be introduced in either the Indian Drugs and Cosmetics Rules or as a schedule to the Rules. Without introducing these measures and requirements as part of either the statutes or regulation it will not be legally correct to issue such a certification.

India has a Federal Structure with 28 states and 7 Union Territories (click here) each having its own local level Food and Drugs administration who issue a manufacturing license for the manufacture of API. The inspectors attached to each of these administration have the legal authority to inspect the manufacturing premises and not the CDSCO which is the Central Authority. This is an additional issue which has not been addressed by the documents issued by the CDSCO and therefore certification by CDSCO that " The manufacturing plant is subject to regular, strict and transparent controls and to the effective enforcement of good manufacturing practice, including repeated and unannounced inspections, so as to ensure a protection of public health at least equivalent to that in the EU" will not be legally appropriate and correct. CDSCO can not give such a certification till appropriate changes are made to the " Indian Drugs and Cosmetics Act and Rules". Merely an interoffice memorandum (click here) issued by MOH, as is the present case, does not have the authority of a statute or a regulation.

The current approach by the CDSCO has given rise to a piquant situation where the local " Indian Food and Drug Administration from each state which issues manufacturing licence has no role to play in the issuance of "written confirmation" for EU exports when in fact it is this agency in each state which is responsible to implement GMP's as per Indian act and the agency which controls and monitors API manufacturers. Therefore the written confirmation is not technically correct and also legally valid as CDSCO will only give the written confirmation and in actual practice not enforce GMP or any other controls.

The document issued as EP-INS- 005 defines deficiencies determined in an audit and classifies them as critical , major and minor. The same document further specifies issuance of a show cause notice and suspension of the " written Confirmation".This is baffling as there is no standard to compare against to classify any deficiency. Further issuance of a show cause notice requires a legislative framework. These actions can not be taken by CDSCO unless these are introduced in the Indian Drugs and Cosmetics Act.

In order for CDSCO to certify that "In the event of findings relating to non-compliance, information on such findings is supplied by the exporting third country without delay to the EU" a GMP standard needs to be in place which is equivalent to EU GMP standard ( = ICH Q 7 or WHO ). The guidance document issued is not a standard. Similarly an announcement only on the CDSCO website that ICH Q 7 will be followed for Inspection does not make it an standard. As mentioned earlier the standard for GMP in India is the Schedule M and Schedule L 1 in the "Indian Drugs and Cosmetics Rules". Unless this standard is changed to be equivalent to ICH Q 7 and WHO , certification by CDSCO that " In the event of findings relating to non-compliance, information on such findings is supplied by the exporting third country without delay to the EU" is not legally correct. Further the regular inspection and monitoring at the state level is done by the provincial or state FDA's and not CDSCO. Therefore it is almost impossible for CDSCO to know violations and non compliances. Further an inspection by provincial FDA will use only the Indian standard and not ICH Q 7 as this not in the Indian regulations. Therefore the local inspectors will never know violations of ICH Q 7 GMP's an API manufacturing plant.

In fact all the guidance documents do not have any legal standing and will not stand a challenge in court of law. Written confirmation based on these documents is an illegal act and also not technically correct as the GMP checklist which will be used for inspection has serous deficiencies as compared to the ICH Q 7 or the WHO guidelines.

So now you have a paradoxical situation where the standards for GMP are Indian Standards and therefore enforcement of the GMP's continues to be done as per the Indian GMP standard by the state/provincial Indian FDA and you have a written confirmation given by CDSCO a central agency with no enforcement authority and which will not oversee implementation of GMP's. Further as this is not legally valid India or the MOH or the CDSCO have no legal liability in case there are serious issues and loss of life by using an API with such a written confirmation. In such a situation if the EU were to raise any issue of a liability , India can easily disown the liability as this certification has no statutory or legal standing. However knowing the Indian political system the person issuing the written confirmation will be the so called "sacrificial lamb".

India first needs to have a Regulatory Standard in place which is equivalent to the EU standard; then have regulations for effective enforcement in place ; then have effective enforcement in place. Once all these pieces are in place, a mechanism needs to be put in place to issue a written confirmation. Though the mechanism to give written confirmation need not be part of Indian Drugs and Cosmetics Act or the Rules, the standard for GMP, mechanism for effective enforcement and transparent controls need to be in the Regulations. Written confirmation cannot be given in isolation without the basics are put in place and actually the standard and enforcement are really equivalent to those in EU. For this India needs to change its statutes, modify the GMP regulations in the Indian Drugs and Cosmetics Act and rules to incorporate the GMP requirements of ICH Q 7 /WHO and introduce regulatory and/or legislative measures for effective enforcement of GMPs before a legally valid certification required by EU directive can be issued.

However this raises another question. Even if India were to put all these regulations in place and were to give a valid certification , why should the Indian Government and the regulators take the responsibility of protecting the Health of people in Europe? I am sure the CDSCO and the people who have put the current mechanism in place have not taken the opinion of the Law ministry on risks and liability which India may have to face as result of such a certification.

EMA needs to evaluate the current approach adopted by India to issue written confirmations and give its recommendations so that India can take corrective actions to meet the EU requirements. Similarly the CDSCO needs to involve the Law ministry before giving such a certification.