FPP Assessment and Deficiencies Lynda Paleshnuik Training workshop: Assessment of Interchangeable...

FPP Assessment

and DeficienciesLynda Paleshnuik

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

OverviewOverview

FPP = Finished Pharmaceutical Product

CTD organization of the FPP

Common deficiencies on a section-by-section basis

Dossier assessment tips (FPP)


CTD Structure of FPP SectionsCTD Structure of FPP Sections

2.3.PDRUG PRODUCT

2.3.P.1 Description and Composition of the Drug Product

2.3.P.2 Pharmaceutical Development

2.3.P.3 Manufacture

2.3.P.4 Control of Excipients

2.3.P.5 Control of Drug Product

2.3.P.6 Reference Standards or Materials

2.3.P.7 Container Closure System

2.3.P.8 Stability


P.1 Description and Composition P.1 Description and Composition

Provide description and composition of the FPP, including:

Composition, i.e., list of all components of the dosage form, and their amount on a per-unit basis (including any overages), the function of components, and their quality standards (e.g., compendial or manufacturer’s specifications)

Description of accompanying reconstitution diluent(s); and

Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable.


P.1 Common DeficienciesP.1 Common Deficiencies

Description is incomplete (should be as in FPP specifications) and/or is not in agreement with sample.

The composition has errors:– Not in agreement with the master production records– Totals don’t add up– Solvents should be listed in the table, but amounts per unit

should not be included or added to the totals– All components used in manufacture should be listed, eg

Nitrogen

The qualitative composition of mixtures, such as Opadry colourants, capsule shells, printing ink, is not provided.


P.2 Pharmaceutical Development P.2 Pharmaceutical Development

This section should:

- contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application.

- CQA/CPP: identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and drug product quality.


P.2.1 Components of the Drug Product P.2.1 Components of the Drug Product

P.2.1.1 Drug Substance

The compatibility of the API with excipients should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed.

For combination products, discuss API-API compatibility.

P.2.1.2 Excipients

Discuss the choice of excipients, their concentration, and characteristics that can influence the FPP performance.


P.2.1 Common DeficienciesP.2.1 Common Deficiencies

API-excipient compatibility: note that if an excipient is in the comparator, the compatibility of that excipient may be considered established. The applicant should therefore include in the dossier the qualitative composition of the comparator product(s).

Guidance on study design is provided in TRS 929 appendix 3 Table A.1 (2005) and Supplement 2 (2006).

Compatibility studies often report appearance only. Studies should include chromatographic results (potency and impurity).


P.2.2 Drug ProductP.2.2 Drug Product

P.2.2.1 Formulation Development

- A brief summary describing the development of the drug product

- Differences between clinical/BE formulations and the proposed formulation should be discussed.

- Results from comparative in vitro studies (e.g., dissolution) should be discussed.

P.2.2.2 Overages – justify any overages

P.2.2.3 Physicochemical and Biological Properties

Parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties should be addressed.



Overages are only acceptable for the API.

Overage of the API in order to extend the shelf-life is unacceptable.

The acceptable justification for an overage of the API is loss of API during manufacture.

This can be justified by showing that batches containing an overage have a potency value of close to 100% at release.


P.2.2 Common Deficiencies, Cont’dP.2.2 Common Deficiencies, Cont’d

Justification for the presence, choice and amount of preservative is absent.

From WHO Generics guideline:

“Usually, in this phase the microbial challenge test could be performed to establish and justify the amount of the antimicrobial preservatives to be used. For this purpose, the drug product should be formulated with different concentrations of preservatives and a microbial challenge test on each of the formulations will give the answer on the “least necessary” but still effective concentration.”


P.2.3 Manufacturing Process Development P.2.3 Manufacturing Process Development

The selection and optimisation of the manufacturing process, in particular its critical aspects, should be explained. Where relevant, the method of sterilisation should be explained and justified.

Differences between the manufacturing process(es) used to produce the BE batch and the proposed process should be discussed and justified, where differences may influence the performance of the product.



Differences between the manufacturing process(es) used to produce the BE batch and the proposed process were not discussed and justified.

This is a significant issue, as the proposed manufacturing process must be representative of that used to manufacture the biolot.

For this reason, a comparison of the executed records of the biolot, and proposed master records should be performed.


P.2.4 Container Closure System P.2.4 Container Closure System

The suitability of the container closure system used for the storage, transportation (shipping) and use of the drug product should be discussed, including:

- choice of materials,

- protection from moisture and light,

- compatibility of the materials with the FPP (including sorption to container and leaching),

- performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).



It must be clear whether the FPP is manufactured and packaged at the same site.

If not, shipping of bulk product is required, and this should be validated:

– Studies in the bulk container, representative of shipping conditions

– Information on the container components for bulk shipping


P.2.5 Microbiological Attributes P.2.5 Microbiological Attributes

Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.



For solid orals, skip testing for microbial limits may be acceptable if the negative results of at least 5 production batches are submitted.


P.2.6 CompatibilityP.2.6 Compatibility

The compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labeling.



This section includes data only on compatibility with reconstitution diluents, or devices.

Data on API-excipient, and API-API compatibility should be in section P.2.1.1.


P.3 ManufactureP.3 Manufacture

P.3.1 Manufacturer(s)

The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

P.3.2 Batch Formula

A batch formula should be provided that includes a list of all components of the FPP to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.



P.3.3 Description of Manufacturing Process and Process Controls

A flow diagram giving the steps of the process and where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.

A narrative description of the manufacturing process should be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail.

Appropriate process parameters such as time, temperature, or pH should be identified. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated.



Equipment should, at minimum, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant.

Proposals for the reprocessing of materials should be justified.

Information should be confirmed to be in agreement with the proposed master production records.



P.3.4 Controls of Critical Steps and Intermediates

Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps of the manufacturing process, to ensure that the process is controlled.

Intermediates: quality and control of isolated intermediates should be provided.

3.2.P.3.5 Process Validation and/or Evaluation

Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g., validation of the sterilisation process or aseptic processing or filling).



The frequency of in-process testing should be specified.

Process controls should be appropriate:

- granulations: moisture (range), blend uniformity, as necessary: bulk and tapped densities, particle size distribution;

- tablet cores: average weight, weight variation, hardness, thickness, friability, disintegration

- coated tablets: weight gain during coating;



adequacy of process validation protocol:

- identification of critical equipment and process parameters,

- definition of testing parameters,

-sampling plans,

-analytical procedures,

- acceptance criteria,

- confirmation that three consecutive, production-scale batches of this drug product will be subjected to prospective validation, or, for sterile products, adequacy of results provided.


P.4 Control of Excipients P.4 Control of Excipients

P.4.1 Specifications

P.4.2 Analytical Procedures

P.4.3 Validation of Analytical Procedures

P.4.4 Justification of Specifications

P.4.5 Excipients of Human or Animal Origin

For excipients of human or animal origin, information should be provided regarding adventitious agents (e.g., sources, specifications; description of the testing performed; viral safety data). (Details in 3.2.A.2).


P.4 Control of ExcipientsP.4 Control of Excipients

P.4.6 Novel Excipients (name, dosage form)

For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. (Details in 3.2.A.3).



Specifications should be those of the FPP manufacturer.

Reference to a compendial monograph may be accepted if compendial standard with no additional tests.

All components of the manufacture, whether they appear in the final product, should be discussed (eg nitrogen, solvents)

Excipients from natural sources should have adequate microbial tests and limits


P.4 Common Deficiencies Cont’dP.4 Common Deficiencies Cont’d

For certain excipients, declarations with respect to the BSE/TSE risk are required from the suppliers where the excipients are of human/animal origin:

Stearic acid, Magnesium stearate and other stearates– If from plant origin, a statement to this effect will suffice

Gelatin

Phosphates from animal origin (eg should be asked for dibasic calcium phosphate)

(Lactose is exempted from this requirement.)



Attestation (eg for API):

You are requested to provide an attestation that your API is not manufactured from reagents obtained from sources that are at risk of transmitting Bovine Spongiform Encephalopathy(BSE)/Transmissible Spongiform Encephalopathy(TSE) agents.


P.5 Control of Drug Product P.5 Control of Drug Product

P.5.1 Specification(s)

P.5.2 Analytical Procedures

P.5.3 Validation of Analytical Procedures

P.5.4 Batch Analyses

A description of batches and results of batch analyses should be provided.

P.5.5 Characterisation of Impurities

Information on impurities if not provided in "3.2.S.3.2 Impurities".

P.5.6 Justification of Specification(s)



The FPP specification provided should be from the company responsible for release testing

The specification should include a reference number, version, date, and appropriate standard

The specification should be dated and signed by authorized personnel (i.e., the person in charge of the Quality Control department)



The specification should include all standard drug product tests and limits for that dosage form

- Solid orals: description, identity, uniformity of dosage units, potency, related compounds, dissolution, microbial limits...

If the tablet contains a score (justified), a one-time study of uniformity of tablet halves should be provided.



Methods and Validation

Copies of the House analytical procedures (and accompanying validation) should be provided,

Adequate system suitability tests should be included.

Results of studies justifying the choice of in vitro dissolution or drug release conditions (apparatus, rotation speed, medium) and demonstrating its sensitivity to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.


P.6 Reference Standards P.6 Reference Standards

Information on the reference standards or reference materials used for testing of the drug product should be provided, if not previously provided in "3.2.S.5 Reference Standards or Materials".


P.7 Container Closure System P.7 Container Closure System

A description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included where appropriate.

For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.

Suitability information should be located in 3.2.P.2.



Specifications (from manufacturer/packager, not supplier) should include identity (IR) of materials in contact with the drug.

Plastics should meet USP <661> tests (one-time study).

Other requirements depending on the FPP form.


P.8 StabilityP.8 Stability

P.8.1 Stability Summary and Conclusion

Summary of the types of studies conducted, protocols used, and the results of the studies. The summary should include conclusions with respect to storage conditions and shelf-life, and if applicable, in-use storage conditions and shelf-life.

P.8.2 Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided.

P.8.3 Stability Data

Results of the stability studies should be presented (e.g. tabular, graphical, narrative). Information on the methods and validation if different from P.5.


Dossier Assessment - FPPDossier Assessment - FPP

Each item below affects how the dossier assessment should proceed:

Screening/pre-assessment

FPP basic research

Biostudy or biowaiver

FPP form


Screening/Pre-AssessmentScreening/Pre-Assessment

Confirm all screening criteria are met. In prequalification this takes the form of the Technical Screening Template.

If screening criteria are not met, consult. It is possible that an abbreviated review is required or the dossier may be rejected.


FPP Basic ResearchFPP Basic Research

Check for compendial monographs for the FPP:

- PhInt, USP, BP

Check standards claimed by the applicant for FPP.


FPP Basic ResearchFPP Basic Research

Other sources of information:

WHOPARs: http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHOPAR_Index.htm

EPARs: http://www.emea.europa.eu/htms/human/epar/a.htm

FDA approved drug products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Note that these reports can include data on scoring of prequalified/approved products.


Biostudy or BiowaiverBiostudy or Biowaiver

BE report exists? Outcome?

Comparator product:

http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_comparator.htm

Biobatch number/batch size

NB: Never weigh in on bioequivalence unless you are quoting a BE report or BE assessor.


Biostudy or BiowaiverBiostudy or Biowaiver

Where a biostudy/biowaiver has been done, information in the quality assessment report must be with reference to the biobatch. The comparison of biobatch vs proposed production batches is the basis of the quality review. The assessor must establish that the formulation and process (equipment, parameters and controls) are the same or list differences.

To this end, the biobatch records must be compared to the blank production manufacturing records. Significant differences must be justified by the applicant. This is necessary to ascertain that the proposed product is representative of the batch which was shown to be bioequivalent/similar to the comparator product.

If data on the quality of the product is assessed without reference to the biolot, the conclusions regarding quality data are meaningless.


BiowaiversBiowaivers

There are various types of biowaivers:

Different strengths (Dose-proportionality);

Scale-up and post-approval changes;

BCS-based biowaivers;



BCS-based biowaivers in Prequalification;

At this time, only FPP’s containing the following API’s are eligible for biowaivers:

ARV’s: lamivudine, stavudine, zidovudine

TB’s: ethambutol, isoniazid, levofloxacin, ofloxacin and pyrazinamide



BCS-based Biowaiver:

The biowaiver includes comparative dissolution between the test product and comparator product in 3 different pH (1.2, 4.5, and 6.8).

Requirements include the submission of the batch records for the test product.


FPP FormFPP Form

There are different considerations based on the final dosage form. It is wise to check the general chapters for the dosage form to be familiar with the kind of tests/issues associated with this form. As noted with API solubility, an issue with the FPP (eg. PSD for inhalation products) may affect the assessment of the API.

Assemble pertinent guidance documents, such as specific dosage form documents.


FPP Form Sources of information

FPP Form Sources of information

International Pharmacopeia:

http://www.who.int/phint/en/p/docf/

BP 2009 index:

http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf

EDQM Knowledge Database:

http://www.edqm.eu/site/Databases-10.html


Choosing Your Battles:Where to Focus

Choosing Your Battles:Where to Focus

We can always delve deeper. A good assessor also knows where to go lightly.

We can always argue for the importance of any given area. With limited time, our approach must be pragmatic and based on risk/benefit.

We cannot treat everything with equal importance.

Focusing on:

Sections and Documents


Where to FocusSections

Where to FocusSections

FPP (CTD sections):

P.2 Pharmaceutical Development

P.3 Manufacture

P.5 Specifications

P.8 Stability


Where to FocusDocuments


Certain official documents comprise the heart of the dossier. For the FPP these are mainly:

Master production documents and executed records (biobatch).

Process validation protocol/report or annual report.

Signed FPP specifications.

Signed stability protocol.




It must be stated clearly in the assessment report that the official signed documents such as specifications were reviewed, and not just the summarized data (data in summary such as PQIF/QOS).

For example, under the specifications tables in the report, the assessor must state that the tests/methods are in agreement with information in signed documents, or differences should be listed and clarified.

If this is not done, it is not clear if the official documents were reviewed and it is possible that the most important deficiencies are overlooked.




When referring to signed documents, it is important to include the document code including version number. Whenever updated specifications are submitted, scanning the updated version into the report is very helpful for subsequent reviews and creating the final approval letter (SOQR for PQP).


Thank youThank you

FPP Assessment and Deficiencies Lynda Paleshnuik Training workshop: Assessment of Interchangeable...

Documents

Transcript of FPP Assessment and Deficiencies Lynda Paleshnuik Training workshop: Assessment of Interchangeable...