Global regulatory authorities are now on an aggressive mode to ensure safety, quality and efficacy of medicines and medical devices besides ensure harmonization of legal procedures related to drug development, monitoring and ensuring compliance with statutory obligations.
Beginning from USFDA to EMA and other regulatory bodies of developing countries and the scope and challenges of such regulatory organizations in drug development are now ensuring that to increase their inspections drives and issue latest guidance on manufacturing, specification on unique facility identification and insisting on Indian pharma to seek third party audits to resolve data integrity issues.
Need for total compliance with third party audits
Early this year, US FDA has re-emphasized the serious deviations it observed during inspection made in Indian pharma companies. The regulator has been noticing that especially with Indian companies, it did not rely on their capability to resolve the data integrity problems without external support. Now it expects Indian pharma to seek the expertise of third party auditors and consultants to resolve data integrity issues and ensure total compliance.
“For the third party auditor, the task is similar to detective work which is both demanding and not pleasant. The auditors and consultants are also apprehensive on the kind of support they would get from the concerned company. However, this detective is essential in the interests of patient safety, noted US FDA.
A series of workshops were held in India in the past to educate pharma professionals on the indispensability of compliances to keep warning letters at bay.
Quoting a February 2014 Warning Letter, US FDA said that good manufacturing practice (GMP) deviations detected during inspections related to electronic data submissions was elementary and urgently recommended companies to get a third party auditor or pharma consultant. These experts could first perform an in-depth GMP review and ensure data integrity deficits are removed.
In some of the Warning Letters issued in 2014 serious deviations with regard to the handling of electronic data like data manipulation are listed. Most of the Warning Letters issued by US FDA indicated failure by industry to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards as per 21 CFR 211.194(a). It also pressed for authorized personnel to institute changes in master production and control records, as per 21 CFR 211.68(b). Further, companies were found to perform unofficial sample and disregarded the results, but reported outcomes from additional tests. The inspection revealed companies used scratch paper containing critical manufacturing data which did not tally with that of the corresponding official batch records.
In the Warning Letters, FDA defined that pharma consultants should be data integrity experts to identify employees at the site, procedures and behaviour of the management which contributed to cause of GMP deviations while handling electronic data. Efforts to touch base with employees who left the company before, during, these time periods should also be undertaken accordingly.
Further, the third party auditors or consultants needed to identify GMP non-compliance, reveal the identity of managers in charge and to what extent the top and middle management knew about data manipulation. Internal reviews need to be extended to other sites which are known to be involved in violations of GMP-compliance, pointed out US FDA.
According to Kaushik Desai, pharma consultant and Hon. Secretary Indian Pharmaceutical Association (IPA), Indian pharma companies need to take cognizance of the issues by clearly understanding the US FDA expectations from consultants involved to help out data integrity issues. The regulator has also been conducting several workshops and now IPA is also open for collaboration with US FDA to conduct extensive training going by its exposure and experience it has with professionals working in companies in the country.
Draft guidance on cGMP for combination products:
The US FDA has released the draft norms which explains the current good manufacturing practices (cGMP) for combination products. Prior to issuance of the final rule, although cGMP regulations were in place to establish requirements for drugs, devices, biological products, and human cells, tissues, and cellular and tissue-based products, there were no regulations to clarify and explain the application of these requirements for combination products.
The final rule was intended to provide such clarification and specify how compliance with applicable cGMP requirements may be demonstrated. As set forth in 21 CFR part 3, a combination product is a product composed of any combination of a drug, device, or biological product. These are referred to as ‘constituent parts’ of the combination product.
Under 21 CFR 3.2(e), a combination product includes two or more regulated components. They could be physically, chemically, or otherwise combined or mixed and produced as a single entity such as a prefilled syringe or drug-eluting stent.
It could also be two or more separate products packaged together in a single package such as a surgical or first-aid kit.
The final rule clarifies that the cGMP requirements that apply to each of the constituent parts apply to the combination product.
For single-entity and co-packaged combination products, offers two ways to demonstrate compliance with cGMP requirements. Under the first option, manufacturers demonstrate compliance with all cGMP regulations applicable to each of the constituent parts included in the combination product.
Under the second option, manufacturers implement a streamlined approach, demonstrating compliance with either the drug cGMPs (21 CFR part 211) or the quality system (QS) regulation (21 CFR part 820) rather than demonstrating full compliance with both, when the combination product contains both a drug and a device, under certain conditions. These conditions include demonstrating compliance with specified provisions from the other of these two sets of cGMP requirements.
According to Prema Desai, consultant auditor for pharma plants, the norms serve as guidance for Industry and FDA staff. Once implemented, this will be a good guidance for all the industries involved in manufacturing any of the combination products described in the guidance. This guidance explains the final rule on cGMP requirements for combination products for a product composed of any combination of a drug, device, or biological product.
“Though cGMP regulations are in place to establish requirements for drugs, devices, biological products, and human cells, tissues, and cellular and tissue-based products (HCT/Ps), there are no regulations to clarify and explain the application of these requirements to combination products. Now the guidance provides such clarification and specifies how compliance with applicable cGMP requirements may be demonstrated by combination product manufacturers,” she added.
EU GMP enforces revision of rules on premises, equipment & production
The European Union good manufacturing practices (EU GMP) guide which is being made effective from this month focuses on quality risk management and insists use of dedicated manufacturing units for specific products to avoid contamination.
In its revised Chapters 3 and 5 related to premises, equipment & production compels the pharma industry to move to high quality level to stall non-conformity standards.
The new EU GMP guide is in sync with the latest developments where implementation of effective quality management system and operational excellence are mandated, noted pharma industry experts.
The revised Chapter 3 dealing with premises and equipment and Chapter 5 on production of the EU GMP Guide Part I for Medicinal Products for Human and Veterinary Use are now enforced and violations would be noted.
According to the regulator, the changes in Chapter 3 are actually easy to compare. The principles and the Chapters 3.1 - 3.5 and 3.7 - 3.27 are identical. Only Chapter 3.6 now mentions quality risk management for the risk control as well as requirements for the use of dedicated facilities. In addition there are indications on other paragraphs to be considered in Chapter 5 and in the Annexes 2-6. Further, a footnote also refers to the EMA Guideline on Shared Facilities.
In order to ensure that the pharma industry stays compliant to the new guidance, EU has provided an analysis where in a table format it presents a concise summary of the changes and compares the new document with that of the old.
The regulators sees that it would allow the pharma industry to quickly compare it with an existing quality management system and can be used for a GAP analysis which is a self inspection or for audits.
EU GMP Guide Part I, Chapter 5 focuses on Prevention of Cross Contamination in Production and in Chapter 5.17 it is supplemented with the inclusion of a norm on ‘Exception for the production of non-medicinal products with reference to Chapter 3. Further in the same chapter it grossly objects to the manufacture of non pharmaceuticals and has introduced ‘ Prohibition of production and storage of poisons, pesticides and herbicides.’
In Chapter 5.18, it has added regulations for genetic material, active pharmaceutical ingredients (APIs) and also omits mention of hormones and cytostatic drugs.