Post-Notice of Compliance (NOC) Changes: Guidance for quality of veterinary drugs: Appendices

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• Appendix 1: Recommendations for conducting and assessing comparative dissolution profiles
• Appendix 2: Changes to excipients
• Appendix 3: Examples of Level IV changes
• Appendix 4: Glossary

Appendix 1: Recommendations for conducting and assessing comparative dissolution profiles

Recommendations when conducting comparative dissolution profiles:

• The resulting comparative dissolution profiles should be considered similar using the following equation which defines a similarity factor (f₂):
  f₂ = 50 LOG {[1+1/n Σⁿ _t=1 (R_t-T_t)²]^-0.5x 100}
  where R _t and T _t are the percent dissolved at each time point. An f ₂ value between 50 and 100 suggests the 2 dissolution profiles are similar.
• At least 12 units should be used for each profile determination. Mean dissolution values can be used to estimate the similarity factor, f₂. To use mean data, the % coefficient of variation at the earlier point should be not more than 20% and at other time points should be not more than 10%.
• The dissolution measurements of the 2 products (such as test and reference, pre- and post- change, 2 strengths) should be made under the same test conditions. The dissolution time points for both the profiles should be the same, for example, for immediate release products: 15, 30, 45 and 60 minutes, for extended release products: 1, 2, 3, 5 and 8 hours.
• Adequate sampling should be performed until either 90% of drug from the drug product is dissolved or an asymptote is reached. A surfactant may be used with appropriate justification.
• Because f ₂ values are sensitive to the number of dissolution time points, only one measurement should be considered after 85% dissolution of the product.
• If the individual data for both the test and reference products show more than 85% dissolution within 15 minutes, the profiles are considered similar(no calculations are necessary).
• When multi-media dissolution profiles are recommended, these studies should be performed in at least 3 media covering the physiological range (pH 1.2 - 6.8), for example water, 0.1N HCl, and pharmacopoeial buffer media for the test and reference products.
• When delayed-release products (for example, enteric coated) are being compared, it is acceptable to consider either multi-point testing in the acid phase as one of these media, or alternatively for coated products, to compare testing in 3 media once the coating disintegrates (such as pH 4, 5 and 6.8).

Solubility

Solubility is calculated based on the minimum concentration of drug, milligram/ millilitre (mg/mL), in the highest therapeutic dose, determined over the physiological pH range (pH 1.2 to 6.8) and temperature (37 ± 0.5^oC). Highly water soluble drugsare those with a dose/solubility volume of less than or equal to 250 mL. Highest dose is the highest approved therapeutic dose for the drug substance in Canada. If not currently approved in Canada, it should be the highest therapeutic dose proposed in the regulatory submission.

Example: Compound A has as its lowest solubility at 37± 0.5^oC, 1.0 mg/mL at pH 6.8, and is available in 100 mg, 200 mg, and 400 mg strengths. This drug would be considered a low solubility drug as its dose/solubility volume is greater than 250 mL (400 mg/1.0 mg/mL = 400 mL).

Permeability

Evidence should be provided to justify the degree of permeability claimed for the drug substance. This could include information from published literature and/or data from experimental and/or clinical studies.

Appendix 2: Changes to excipients

Notes:

• These percentages are based on the assumption that the drug substance in the product is formulated to 100.0% of label/potency. The total additive effect of all excipient changes should be not more than 5.0%.
• Multi-functional Excipients: If an excipient provides multiple functions (for example, microcrystalline cellulose as a filler and as a disintegrant), then the most conservative recommended range should be applied (±3.0% for microcrystalline cellulose should be applied in this example). If a wider range is proposed, scientific justification, including supporting data to demonstrate that the wider range will not affect the other function of the excipient should be provided.
• Bracketing: If different strengths of an immediate release solid oral dosage form have differences in the proportion of excipients which exceed those in the above table, but within the progression of strengths, the changes are incremental, a comparative bioavailability study should be performed on the lowest and highest strengths. Incremental changes are those in which proportions of excipients increase or decrease successively from the lowest to the highest strengths in the range.
• If different strengths contain different excipients, or if the differences in the proportion of excipients exceed those defined in the above table and are not incremental within the progression of strengths, comparative bioavailability studies should be performed on each strength.
• Pharmacokinetic Considerations: It should be noted that the pharmacokinetic characteristics of the medicinal ingredient (such as linear kinetics or non-linear kinetics with greater than or less than proportional increases in area under the curve (AUC) with increasing dose), will also be taken into consideration during the evaluation of a request for a waiver of the requirement to conduct clinical or comparative bioavailability studies on the basis of proportionality of additional proposed strength(s) to the strength used in the in vivo studies.

Appendix 3: Examples of Level IV changes

• Non-critical changes to the licensed application including spelling mistakes, editorial changes made to documents such as Validation Summaries and/or Reports, Analytical Procedures, SOPs, Production Documentation Summaries, QOS, for added clarity that have no impact to affect the safety, efficacy and quality of the product.
• Change in stopper cap colour for an injectable product.
• Modification to pretreatment stages of a WFI system, including purified water systems used solely for pretreatment in WFI production.
• Change in the floor plan that does not affect production process or contamination precautions.
• Addition of vial reject chute.
• Change in the in-process controls performed at non-critical manufacturing steps or change to a non-critical manufacturing area (see Glossary).
• Rooms upgrades, such as installation of improved finishes on floors/walls.
• Addition of a new GMP storage warehouse for raw materials, master and working cell banks and drug substance.
• Installation of non-process-related equipment or rooms to improve the facility, such as warehousing refrigerators or freezers.
• Replacement of equipment with an identical equipment.
• Change in specifications for a compendial raw material to comply with an updated Schedule B pharmacopoeial standard/monograph.
• For veterinary biologics, with the exception of a potency assay or a bioassay, transfer of the QC testing activities for a pharmacopoeial assay to a different laboratory within the same building, to a different building within the same company or to a different company listed on the sponsor's establishment licence.
• Change in supplier for non-critical excipients.
• Change in tertiary packaging components of drug substance or drug product that do not affect stability.
• Change in the name of the drug product manufacturing site.

Appendix 4: Glossary

Acronyms

ASMF

Active Substance Master File

ANDS

Abbreviated New Drug Submission

BRDD

Biologic and Radiopharmaceutical Drugs Directorate

BSE

Bovine Spongiform Encephalopathy

CQA

Critical Quality Attribute

CTD

Common Technical Document

DMF

Drug Master File

EDQM

European Directorate for the Quality of Medicines of the Council of Europe

EL

Establishment Licence

GMP

Good Manufacturing Practices

HC

Health Canada

HVAC

Heating, Ventilation, Air Conditioning

ICH

International Council for Harmonisation

INN

International Non-proprietary Name

IVIVC

in-vitro, in-vivo correlation

NC

Notifiable Change

NDS

New Drug Submission

NOC

Notice of Compliance

PDD

Pharmaceutical Drugs Directorate

QC

Quality Control

Q8(R2)

ICH guideline entitled "Pharmaceutical Development"

Q9(R1)

ICH guideline entitled "Quality Risk Management"

Q10(R1)

ICH guideline entitled "Pharmaceutical Quality System"

Q11

ICH guideline entitled "Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)"

SANDS

Supplement to an Abbreviated New Drug Submission

SNDS

Supplement to a New Drug Submission

TSE

Transmissible Spongiform Encephalopathy

VDD-CPID

Veterinary Drugs Directorate Certified Product Information Document.

VDD-QOS

Veterinary Drugs Directorate Quality Overall Summary

VICH

International Council for Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products

WFI

Water for Injection

WHO

World Health Organization

Definitions

Adjuvant:

Component that potentiates the immune responses to an antigen and/or modulates it towards the desired immune responses. Adjuvant may be of pharmaceutical origin (chemical/synthetic adjuvant) or of biological origin (biological adjuvant).

Batch:

A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, produced according to a single production order and as attested by the signatories to the order. In the case of continuous manufacture, a batch corresponds to a defined fraction of the production that is characterised by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.

Biological auxiliary material:

Raw material from a biological source which is intended to be used as a processing aid in the fabrication of the drug. It may be absent from the drug or may remain as an impurity in the drug at the end of the manufacturing process (for example, biological additives used to supplement cell culture medium in production fermenter, human antithrombin III used to complex and remove human thrombin).

Biological starting material:

Raw material from a biological source which is intended to be used in the fabrication of a drug and from which the active ingredient is derived either directly (such as plasma derivatives, ascitic fluid, bovine lung) or indirectly (such as cell substrate, host/vector production cells, eggs, viral strains).

Carrier:

An edible material (such as calcium carbonate, rice hull, corn cobs, gluten) to which drug substances are added to form a homogenous drug premix or is used to dilute the drug premix (or medicated premix) to form medicated feed.

Certificate of suitability (CEP):

A certificate of compliance of a substance with the relevant requirements of the European Pharmacopoeia monographs for use in medicinal products issued by the European Directorate for the Quality of Medicine of the Council of Europe (EDQM).

Container closure system:

The sum of packaging components that together, contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system.

Control Strategy:

A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Change-over procedure:

A logical series of validated steps that ensures the proper cleaning of suites and equipment before the processing of a different product begins.

Closed process/closed system:

Process equipment or process step in which the product is not exposed to the external environment. A closed system requires that the quality of materials entering or leaving the system and the manner in which these materials are added/removed from the system is carefully controlled.

Critical manufacturing step:

A manufacturing process/step that may result in a potential change in the purity/impurity profile or due to the nature of the starting materials or resulting product/intermediate, requires containment within a specially designed manufacturing area or production facility, for example, the development and preparation of cell banks and seed lots, initial propagation, scale-up, blood and plasma pooling and fractionation, fermentation, harvesting, inactivation, purification, addition of adjuvants or preservatives, the conjugation and pooling of bulk concentrates and the final preparation of drug product including concentration/diafiltration, formulation, sterile filtration, filling and lyophilization.

Critical process parameter:

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Critical Quality Attribute:

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Delayed release:

Release of a drug (or drugs) at a time other than immediately following oral administration.

Dilute drug premix:

A drug for veterinary use that results from mixing a drug premix with a feed as defined in section 2 of the Feeds Act, to such a level that at least 10 kg of the resulting mixture is required to medicate one tonne of complete feed, as defined in section 2 of the Feeds Regulations , 1983, with the lowest approved dosage level of the drug.

Design space:

The multidimensional combination and interaction of input variables (such as material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

Different host/media-type:

Mammalian cells or any micro-organisms involved in the manufacture of a drug substance which are different from the existing hosts in the facility or use a cell culture or fermentation medium with significantly differing composition.

Discrete chemical entity:

A single molecular entity with a known chemical structure.

Dosage form:

A drug product that has been processed to the point where it is now in a form in which it may be administered in individual doses.

Drug product:

The dosage form in the final immediate packaging intended for marketing.

Drug substance:

The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Drug substance intermediate:

A material produced during steps in the synthesis of a drug substance that must undergo further molecular change or processing before it becomes a drug substance

Equivalency of method:

The proposed analytical method has been validated and demonstrated to be equivalent to the approved method in terms of suitability for its intended use.

Equivalent equipment:

Equipment with similar design and same operating principle and fabricated with product-contact material of same or higher grade quality. Equivalent equipment should give a product of same quality as the one processed by the previous equipment.

Excipient:

Anything other than the drug substance in the dosage form.

Extended release:

Extended release products are formulated to make the drug available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (for example, as a solution or an immediate release dosage form).

Facility:

A building in which a specific manufacturing operation or multiple operations take place.

Feed ingredient:

Any substance or mixture of substance that is assessed or evaluated as being acceptable for use in feeds.

Feed microtracers:

Microtracers are uniform stainless steel particles coloured with codified food dyes and incorporated into a drug premix (medicated premix). Microtracers are used in feed assays to establish correlation between drug and microtracer recoveries to give an easy and rapid method for semi quantitative detection of the medicated premix in the medicated feed, and the validation of mixing process in a field environment.

Fermentation train:

Equipment and conditions involved in the stepwise expansion of the cell culture process.

Functional secondary packaging:

Packaging material not in direct contact with the product that provide additional protection or serve to deliver the product.

HVAC (Heating, Ventilation, and Air Conditioning):

Industry term for the systems and technology responsible for the heating, ventilation, and air conditioning in buildings. HVAC systems regulate comfort (temperature and humidity), energy efficiency, and air quality.

Immediate release dosage forms:

Dosage forms that allow the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.

In-process control:

Check performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as part of in-process control.

Interchangeable:

Where such status is indicated, any of the official texts from JP, EP, or USP can be substituted one for the other (appropriately referenced) in the ICH regions for purposes of the pharmaceutical registration/approval process. Using any of the interchangeable methods, an analyst will reach the same accept or reject decisions irrespective of which PDG pharmacopeia is used.

Medicated feed:

A mixed feed that contains a medicating ingredient [2.(1) of the Feeds Regulations, 1983].

Medicated premix (or drug premix):

A drug for veterinary use to which a drug identification number has been assigned, where the directions on its label specify that it is to be mixed with feed as defined in section 2 of the Feeds Act. (C.01A.001 of the Food and Drugs Regulations). It is a veterinary drug product prepared in advance with a view to the subsequent manufacture of medicated feeds.

Modified release dosage forms:

Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products.

Multi-product facility:

A facility where more than one product of the same type or products from different classes are fabricated (such as pharmaceutical and biological drugs).

Non-critical area:

Area that does not encompass process steps.

Non-critical excipient:

Excipient with no active function, for example, a solution used to adjust pH.

Non-critical manufacturing step:

A manufacturing process/step that has no impact upon purity and impurity profile or requires no specific facility considerations, for example, buffer and media preparation, storage of intermediates, and packaging (note that some biological drugs may require critical temperature and/or light control during packaging).

Open system:

Any steps in a manufacturing process where in-process materials or components are exposed to the external environment.

Pilot scale:

A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.

Presentation:

Container that contains the drug product. The container may be used directly or indirectly in the administration of the drug (such as vials, pre-filled syringes, pre-filled pens).

Primary container closure component:

Packaging material in direct contact with the product.

Proposed drug substance/drug product:

Drug substance and/or drug product manufactured using a process incorporating the proposed change(s).

QC approved documents:

"QC approved" means approved by the person in charge of the quality control department.

Reprocessing:

Subjecting all or part of a batch or lot of an in-process drug, a bulk process intermediate (final biological bulk intermediate) or a bulk drug of a single batch/lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications.

Schedule B pharmacopoeia:

Pharmacopoeia listed in Schedule B of the Food and Drugs Act (such as United States Pharmacopeia, European Pharmacopoeia).

Shelf-life (also referred to as expiration period):

The time period during which a drug product or drug substance is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.

Starting material:

A starting material is a raw material, intermediate, or a drug substance that is used in the production of a drug substance and that is incorporated as a significant structural fragment into the structure of the drug substance.

Strength:

Quantity of medicinal ingredient in a particular dosage form. For solution, concentration of the active pharmaceutical ingredient multiplied by the fill volume.

Release controlling excipient (or agent):

An excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form.

Unexpected events:

"Unexpected events arising during manufacture or because of stability concerns" refers to unexpected events resulting in a failure to meet specifications.

Validation:

The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.

Withdrawal period:

The length of time between the last administration of a drug to an animal and the time when tissues or products collected from the treated animal for consumption as food contain a level of residue of the drug that would not likely cause injury to human health.

Withholding time:

The length of time, specified in 12-hour milking intervals, up to a maximum of 8 intervals (96 hours) that must elapse after treating a lactating animal with a veterinary drug before milk can be collected for human consumption.