05/03/2023 DILIP NAMA 1

REGULATORY UPDATES

Presented By Dilip Nama

AM QANectar Lifescience Ltd.

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REGULATORY UPDATESList of updates in year 2015

• FDA New guidelines• FDA revised guidelines• Eudralex new guidelines• Eudralex revised guidelines• WHO guidelines• Gazette of india

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ICH announces organizational changes

• On its inaugural meeting on 23 October 2015 the International Council for Harmonisation (ICH), formerly the International

• Conference on Harmonisation (ICH), announced organisational changes:• ICH emphasizes that it is a truly global initiative and more involvement of

regulators around the world is welcomed andexpected, as they will be invited to join counterparts from Europe, Japan, USA, Canada and Switzerland. This is aligned with the possibility of wider inclusion of global industry sectors affected by ICH Harmonisation.

• In addition, a more stable operating structure is achieved through the establishment of an ICH association, a legal entity under Swiss law, which will facilitate future growth through the participation of new members.

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Method validation(31th July 2015)• Unlike the previous Guideline from 2000, the new document

explicitly mentions biologics in its title.• When comparing it with the former and now invalid "Methods

Validation" Guidance, it is apparent that the Draft Guidance has been kept much shorter. There are no detailed descriptions available:

• for example the table about recommended validation parameters for different analytical tests has been deleted without substitution. Yet, new chapters have been added, like chapter "VIII.

• Life cycle management of analytical procedures" and its following chapter on the verification of analytical methods in FDA's own laboratories ("IX: FDA methods verification").

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Request for Quality Matrics• In the last months, the U.S. Food and Drug Administration

(FDA) has set up an initiative to use Quality Metrics for planning their risk based inspections.

• This development was triggered by the Food and Drug Administration Safety and Innovation Act (FDASIA; Title VII, section 706).

• The goal of the Guidance is to give FDA the authority to collect Quality Metrics from production sites supplying APIs, medicinal products, Biotech, OTC etc. to the US.

• They should provide data about the "quality level" in each manufacturing site. By this, FDA wants be able to see how well quality systems are maintained.

cont…

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Request for Quality Matrics• In the future companies will need to conduct continual

monitoring, assessment and reporting on the state of quality across their drug products and facilities regulated by FDA.

• This should then enable FDA to schedule inspections based on risk assessment, improve the efficiency and effectiveness of these inspections and also reduce product-related shortages and recalls.

• FDA also wants to "encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing".

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Request for Quality Matrics• What needs to be reported?• FDA asks for data to be compiled and reported on:• The number of lots attempted of the product.• The number of specification-related rejected lots of the product (during or after

manufacturing).• The number of attempted lots pending disposition for more than 30 days.• The number of OOS results for the product, including stability testing.• The number of lot release and stability tests conducted for the product.• The number of OOS results for lot release and stability tests for the product which are

invalidated due to lab error.• The number of product quality complaints received for the product.• The number of lots attempted which are released for distribution or for the next stage of

manufacturing the product.• If the associated APRs or PQRs were completed within 30 days of annual due date for the

product.• The number of APRs or PQRs required for the product.• .

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Request for Quality Matrics• FDA intends to calculate the following Quality Metrics for each product and

establishment (where applicable):• Lot Acceptance Rate = 1 - x (x = the number of specification-related rejected lots

in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe).

• Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe.

• Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test results divided by the total number of tests performed by the establishment in the same timeframe.

• Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment

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Request for Quality Matrics• Who needs to report?• FDA intends to request the submission of data from establishments that are

required to register under section 510 of the Food, Drug and Cosmetic (FD&C) Act and that are subject to inspection under section 704 of the FD&C Act (704 allows inspections of regulated entities).

• Establishments that receive requests under section 704(a)(4) would be encouraged to submit quality metrics data also for certain foreign establishments that are not required to register.

• So basically the Guidance applies to every legal entity engaged in the manufacture, preparation, propagation, compounding, or processing of a drug product for the US market or an API used in the manufacture of such a drug product. FDA sees the Quality Control Unit (QCU) generally to be the one to compile the reports.

• How many reports should be submitted?• FDA intends to get one report for each finished dosage form and one report

for each API of a covered drug product.

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Request for Quality Matrics• When do the reports should be submitted?• Reports should be submitted after request. Quality metrics data reports should be

submitted for a one-year period that begins after FDA issues its requests. They should then be submitted within 60 days of the end date of the reporting period.

• What will happen in the case of non-reporting?• This will change FDA's risk assessment and may lead to an earlier inspection. In addition,

the respective products may be deemed adulterated and subject to enforcement action.• What are the challenges?• Certainly a challenge for both industry and FDA will be how to span the scope of all

segments like branded, generic, biotech and OTC products, APIs, various finished dosage forms (solid oral, modified release, liquid, sterile, etc. and domestic and foreign products with possible language barriers. This will create a lot of data. And Quality Metrics are just one part of the picture, intended to be enhancing FDA's analysis but not replacing existing measures. The program will likely need to learn and evolve through continuous improvement.

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Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules June 2015

• FDA published a guideline entitled "Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules".

• The Agency saw a need for regulation because of the fact that the dosage forms of generics - particularly tablets and capsules – may considerably differ in shape and size from reference listed drugs (RLD)

• despite of equivalent pharmacological parameters. The FDA is concerned that this could affect patient compliance and acceptability of medication regimens and thus could pose a risk to patient safety.

• This mainly applies to patients suffering from dysphagia. For them swallowing a tablet or a capsule of a larger size may be almost impossible.

• This guidance addresses companies who want to submit a marketing authorisation dossier in the USA either for a generic medicinal product or for an additional strength of an already authorised generic.

• The Guidance doesn't apply to already marketed generics and oral dosage forms otherthan tablets and capsules.

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Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules June 2015

• The Guidance formulates requirements with regard to the dimensions, volume measurements and further physical attributes of tablets and capsules which have to be taken into consideration by the generics manufacturers.

• For example, the largest dimension shouldn't basically exceed 22mm. For smaller dimensions or volumes of the RLD, the generic dosage form may be larger only within specified limits.

• If the physical attributes defined in this Guidance are exceeded, theapplicant should contact the Agency before submitting the authorisation dossier. Studies in the development phase with dosage forms which have physical attributes outside the limits set have to be described in CTD module 3, chapter 3.2.P.2, "Pharmaceutical Development" or 3.2.P.5.6,

• "Justification of Specifications".

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WHO General guidance on hold-time studies

• After the World Health Organisation (WHO) had released the second draft of the guideline for the design of hold-time studies in March already, it now released the final version as part of the Technical Report Series 992 (TRS 992, Annex 4).

• The GMP regulations require that raw materials, packaging materials, intermediate, bulk and finished products need to be stored under suitable conditions.

• This also includes the definition of maximum hold-times for intermediate and bulk products prior to their further processing.

• The definition of these times should be justified on the basis of scientific data.

• This guideline aims at reflecting aspects that may be important in the design of hold-time studies.

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WHO General guidance on hold-time studies• According to WHO, hold-time studies can be part of the development or

also be carried out during the later Scale-Ups. • In any case they should be confirmed during product validation, though.• With coated tablets as an example the guideline demonstrates at what

points in the manufacturing process samples can be taken and examined for durability.

• The number of batches to be examined is supposed to be risk-based. • The times, according to which the listed intermediates could be sampled

and examined are also mentioned exemplary. • Whereas the original draft comprised propositions with regard to

combined hold times - meaning the impact of hold times of various intermediates among one another - they are not part of the final guideline any more.

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Eudralex Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for

excipients of medicinal products for human use• The European Commission has published an important and long-awaited

guideline for appropriate GMP’s for excipients in the official journal of the European Union, edition 21st March 2015.

• The guideline tilted the "formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use" is being published after almost two year of the publication of the draft guidelines.

•The guideline is considerably more detailed in its present form and contains more stringent requirements than the draft guideline. For instance, as part of the risk assessment for pharmaceutical excipients the supply chain , cold chain management, the stability of the excipient and the suitability of the packaging have to be evaluated has now been included.

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Eudralex Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for

excipients of medicinal products for human use

• Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been determined, Ongoing risk review should be performed through mechanisms such as:

• monitoring and trend analysis of excipient quality; • observed organisational, procedural or technical/process changes at the excipient

manufacturer;• Questionnaires;• based on the outcome of the risk review, the established control strategy should be

reviewed and revised if needed.• The requirements for ascertaining and ensuring the appropriate GMP laid down in

the new guidelines are rather challenging as a whole. • The pharmaceutical companies concerned must now extent their risk profiles for

excipients already drawn up according to the new requirements. • Additionally, the appropriate GMP and the required two risk profiles (for the

excipient and the manufacturer of the excipient) must be drawn up for all authorised products.

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Eudralex volume 4 Chapter 3Premises and Equipment

1 March 2015• Prevention of cross contamination• The EU will have new GMP regulations that address

cross contamination on March 1, 2015. Chapters 3 and 5 of Volume 4 of the EudraLex have been updated to provide new guidance on the prevention of cross contamination.

• The current GMPs created are not clear enough and have created confusion in the industry.

• Even regulators have different interpretations.

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Eudralex volume 4 Chapter 3Premises and Equipment

• The current guidance states that “In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (eg. penicillins) or biological preparations (eg. from live microorganisms).

• The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities…”

• The guidance requires interpretation by Industry as well as Regulators regarding the use of dedicated and self-contained facilities for additional products.

• Most have followed a conservative approach and have used dedicated facilities for all these compounds.

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Eudralex volume 4 Chapter 5 Production

• Effective Date:1 March 2015• Will incorporate greater use of Quality Risk Management in the prevention of cross

contamination.• The key to these changes are in addressing cross-contamination in the design,

maintenance and operation of pharmaceutical processes, equipment and facilities, with a particular note on the use of organizational Controls such as campaign manufacture.

• There is less definition of the types of products requiring dedicatedfacilities, however, the requirement for such facilities is still a consideration if the above mentioned controls are in effective or not comprehensive.

• For cleaning validation, toxicological-based limits rather than what are sometimes described as “arbitrary limits” are now required. It is no surprise that Quality Risk Management is the key in mitigating cross-contamination concerns!

• Partial or full testing of starting material (5.35)• Supplier qualification added.

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Chapter 8: Complaints, Quality Defects and Product Recalls• Effective date: 1 March 2015• Complaints, Quality Defects and Product Recalls” has been

overhauled to incorporate the use of Quality Risk Management principles in the addressing Complaints and Recalls.

• Application to product defects is also more clearly defined within the requirements.

• The take home message from this chapter update is that the approach to issue management i.e. CAPA needs to be adopted using all relevant tools and methodologies such as risk assessment and root cause analysis.

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Annexure 15 Qualification and validation

• Effective dated:1 October 2015• The subject Design Space (ICH Q8) is now also covered in the area

Process Validation.• Many risk considerations (ICH Q9) are now mandatory.• The life cycle approach and process knowledge (ICH Q10) are now

included as well. • Third party services are now authorized explicitly if the supplier has

been qualified correspondingly.• This is a positive adaptation to reality. The mention of preliminary

approvals - e.g. in the case of deviations - is good for a next (validation / qualification) stage, if there is a documented assessment showing that there is no significant impact on the next stage.

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Annexure 15 Qualification and validation

• Unfortunately a clear differentiation between qualification (based on equipment and facilities) and validation (related to processes) is missing. This is a shortcoming that unfortunately exists in many European regulations.

• Other important changes compared to the current version are:• There are new terms that are not explained in the glossary, such as

"ongoing validation strategy"• Retrospective validation and the idea of revalidation are gone

completely - except for one exemption(on going validation strategy)• The qualification has become more extensive due to the integration

of user requirements as a separate step and claim for a SAT.(Factory acceptance testing (FAT) /Site acceptance testing (SAT)

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Annexure 15 Qualification and validation

• The naming of transportation verification, packaging validation, validation of utilities and validation of analytical methods are completely new.

• In the Process Validation there are now 2 different approaches - a (modern) "continuous verification" approach and a

• Traditional approach. The latter is still based on the classic 3 validation runs. But in any case, process robustness has to be proven.

• "Bracketing" approaches in the Process Validation are possible now - have to be justified though A hybrid approach between continuous verification and the traditional Process Validation approach remains somewhat "fuzzy”

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Annexure 15 Qualification and validation

• With regard to cleaning validation the 'visibly clean' criterion as the only acceptance criterion is no more acceptable.

• A grouping of equipment in the cleaning validation is explicitly possible now - but needs to be founded

• Acceptance criteria for a cleaning validation depend on toxicological data (permitted daily exposure, PDE)

• The statement that the number of cleaning validation runs has to be decided on the basis of a risk assessment is very interesting.

• The magic 3 is not mentioned explicitly here.• The concept of cleaning verification for rarely manufactured

products is also new.

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Elemental impurity ICHQ3 (9th September 2015)

• The guidance establishes permitted daily exposures for 24 elements in drug products based on evaluation of toxicity data.

• Permitted daily exposures are provided for each element by three routes of administration--oral, parenteral and inhalation.

• The guidance also provides for a risk-based approach to assessing the likelihood that elemental impurities with established permitted daily exposures will be present in a pharmaceutical product.

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Elemental impurity ICHQ3 (9th September 2015) cont…• Q3D Elemental Impurities FDA.pdf• This guidance presents a process to assess and control elemental

impurities in the drug product using the principles of risk management as described in ICH Q9.

• This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.

• The guidance applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or nonrecombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guidance, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides

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Bar-coding system

• http://www.egazette.nic.in/• Public notification no. 12/2015-2020 new

delhi dated 22 may, 2015• Bar-coding on secondary and tertiary pack is

compulsory

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The revised USP General Chapter <661> (Containers-Plastics)

• Will be published in USP 39-NF34 with an official date of May 1, 2016.• Including Changes to the title of General Chapter <661> (new title: Plastic

Pckaging Systems and their Materials of Construction), sections of General Chapter <661> moved into new General Chapters <661.1> (Plastic Materials of Construction) and <661.2> (Plastic Packaging Systems for Pharmaceutical Use).

• The General Chapter <661.1> gives information on the comprehensive characterization of a plastic material, while General Chapter <661.2> covers testing methods and standards for pack aging systems made of plastic.

• The Drafts of the above mentioned General Chapters were proposed for comment in Pharmacopeial Forum 39(5) and 40(5).

• All modifications will become official on May 1, 2016.• Additionally, a Draft of a new USP General Chapter <1661> (Evaluation of Plastic

Packaging Systems and their Materials of Construction with respect to their user safety impact) was proposed in Pharmacopeial Forum.

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EU-GMP Guideline Annex 16 "Certification by aQualified Person and Batch Release".

• Deadline for coming into operation is 15 April 2016.• As one important topic, it has been pointed out that the major task of a Qualified

Person (QP) is the certification of a batch for• its release. In this context, the QP must personally ensure the responsibilities listed

in chapter 1.6 are fulfilled. In chapter 1.7• a lot of additional responsibilities are listed which need to be secured by the QP. The

work can be delegated and the QP can rely on the respective Quality Management Systems. However "the QP should have on-going assurance that this reliance is well founded" (1.7). Amongst these twenty-one tasks are for example:

• Starting materials comply and the supply chain is secured, including GMP assessments by third parties

• The necessary audits have been performed and the audit reports are available• Manufacturing and testing performance are compliant with the MA• Manufacturing and testing processes are validated• Changes have been evaluated and investigations completed

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EU-GMP Guideline Annex 16 "Certification by aQualified Person and Batch Release".

• It is important to mention in this context that "the ultimate responsibility for the performance of an authorised medicinal product over its lifetime; its safety, quality and efficacy lies with the marketing authorisation holder (MAH).

• However "the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force (…),

• in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)" (seeGeneral Principles).

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Revision of the ICH Guideline Q3C• ICH Q3C divides solvents into 4 classes:• Class 1: Solvents to be avoided. These substances are highly toxic, in some

cases genotoxic or harmful to the environment and should not be used. If their use is unavoidable, the stated limit values must be observed.

• Class 2: Solvents to be limited. These solvents are toxic in certain concentrations but can be tolerated below their maximum permitted daily doses (PDE values).

• Class 3: Solvents with low toxic potential. The intake of these solvents is uncritical in quantities of up to 50 mg per day without any significant health risk. However there are no long-term toxicology studies for most of these solvents.

• Class 4: Solvents for which no adequate toxicological data was found. According to ICH Q3C manufacturers of active

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Revision of the ICH Guideline Q3C• In June this year the ICH published a further revision as a

"Draft Consensus Guideline" ICH Q3C(R6)" (Step 2 document). • The document contains the following changes:• Reassessment of methyl isobutyl ketone (MIBK): In more

recent studies, a higher toxic potential was determined• compared to the data from older studies. As a result, MIBK

was reclassified from class 3 to class 2.• Addition of triethylamine to the guideline: This solvent is

frequently used due to its favourable solubility properties, which allows it to catalyse certain chemical reactions. Based on the latest toxicological data, it is classified under class 3.