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The whole pharma world goes berserk in meeting the ‘product specifications’ as required by various regulatory authorities. Pharmacopeial specifications, In-house specifications, product specific specifications are various types of specifications that are required to be met by a product before release in the market. In pharmacopeial specifications also, every country and it’s regulator relies on different pharmacopeias viz. USP, BP, IP, CP, FP, EP, JP etc. More often manufacturers are confused w.r.t. specifications of API and it’s resultant finished formulations.
While discussing about specifications various questions pop-up in our mind, such as:
What are release and shelf-life specifications? How are these different from each other? How to develop specifications?
All these questions and many others are explained below:
What is a specification?
The International Conference on Harmonization (ICH) defines specifications as “a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described.”
Specification is a critical quality standard that establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. The specifications are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.
Which products are considered to be non-conforming to specifications?
The APIs (drug substances) and/or finished formulations (drug products) which failed to meet the listed acceptance criteria when tested for listed analytical tests according to the approved analytical procedures.
Does specification help to characterize the product?
Specifications are developed to ensure the quality, safety and efficacy of the product. They are not intended to provide complete characterization of the product.
Product is meeting all the specifications. Does it necessarily mean that product is of good quality and is safe and efficacious?
The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, and process validation, and by specifications applied to them throughout development and manufacture.
Specifications are only a small part of total control strategy for the drug substance and drug product designed to ensure product quality and consistency. Other parts of this strategy include thorough product characterization during development, upon which specifications are based, and adherence to Good Manufacturing Practices; e.g., suitable facilities, a validated manufacturing process, validated test procedure, raw material testing, in-process testing, stability testing, etc.
How specifications are developed?
The specifications for raw materials, intermediates, packaging components, in-process materials and the finished product are first established during the drug development process. Initially, during the specification development, the focus is on product safety.
Specifications are something which are constantly evolved as during the early stages of product development, the firms have very limited knowledge and experience w.r.t. product. Lot of experience is gained and data is generated after the product launch, which may lead to revision of specifications to include additional quality characteristics.
The final specifications are used to assess the quality and performance of the drug substance, excipients, container closure systems, intermediates, and drug product to ensure safety and efficacy. The finalized specifications are approved by regulatory authority.
How specifications are justified?
Inclusion of each test, its procedure and acceptance criterion in a specification shall be thoroughly justified. The justification should be referred to relevant development data, pharmacopeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long-term stability studies, as appropriate. Additionally, a reasonable range of expected analytical and manufacturing variability should be considered.
Test results from stability and scale-up / validation batches, with emphasis on the primary stability batches, should be considered in setting and justifying specifications. In case of limited initial experience with the manufacture of the drug substance or drug product at any particular site, data from other site manufacturing same product may also be referred to. Justification for proposing exclusion of a test from the specification should be based on development data and on process validation data.
What are various criteria for establishing specification?
Following are the categories of requirements that shall be considered when establishing specifications for a particular material, component, or product:
- Pharmacopeial requirements: Quality attributed, test methodology, and acceptance criteria that have been established by national or international pharmacopeia. Pharmacopeial requirements establish the base or the minimum quality standards for evaluating a material. Additional quality attributes and tests may be necessary to ensure that the material is fit for its intended use.
- Regulatory requirements: Quality attributes and acceptance criteria that are well defined by regulatory agencies (for example, specifically identified in regulatory guidance).
- Product-specific requirement: Quality attributes and acceptance criteria that are unique and critical to the material or product itself.
A specification normally comprises of following two types of test:
Universal Tests: Tests which are applicable to all drug substances and drug products irrespective of the material.
Product Specific Tests: Tests which are unique to the substance/ product itself or the specific form of the drug substance/ drug product.
What are various types of tests to be included in Raw Material/ Drug Substance specifications?
The specifications shall include following universal and product specific tests. Additional tests as deemed fit may also be included.
| S. No. | Type of Test | Test | Remarks |
| 1 | Universal Tests | Description |
Qualitative statement about the state (e.g. solid, liquid) and color of the new drug substance |
| 2 | Identification |
Test(s) shall be able to discriminate between compounds of closely related structure which are likely to be present. Identification tests should be specific for the new drug substance e.g. infrared spectroscopy. Identification solely by a single chromatographic retention time, for example, is not regarded as being specific. However, the use of two chromatographic procedures, where the separation is based on different principles or a combination of tests into a single procedure, such as HPLC/UV diode array, HPLC/MS, or GC/MS is generally acceptable. If the new drug substance is a salt, identification testing should be specific for the individual ions. |
|
| 3 | Assay |
A specific, stability-indicating procedure should be included to determine the content of drug substance. In many cases, it is possible to employ the same procedure (e.g., HPLC) for both assay of the drug substance and quantitation of impurities. |
|
| 4 | Impurities | Test (s) for Organic and inorganic impurities and residual solvents | |
| 5 | Product Specific Tests | Physicochemical properties |
Properties such as pH of an aqueous solution, melting point / range, and refractive index. The procedures used for the measurement of these properties are usually unique and do not need much elaboration, e.g., capillary melting point, Abbé refractometry. The tests performed in this category should be determined by the physical nature of the drug substance and by its intended use. |
| 6 | Particle size |
Particle size have a significant effect on dissolution rates, bioavailability, and / or stability. In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided. |
|
| 7 | Polymorphic forms |
Some drug substances exist in different crystalline forms which differ in their physical properties. Differences in these forms could, in some cases, affect the quality or performance of the drug products. Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist. Examples of these procedures are: melting point (including hot-stage microscopy), solid state IR, X-ray powder diffraction, thermal analysis procedures (like DSC, TGA and DTA), Raman spectroscopy, optical microscopy, and solid state NMR |
|
| 8 | Microbial limits |
The type of microbial test(s) and acceptance criteria are based on the nature of the drug substance, method of manufacture, and the intended use of the finished dosage form manufacture with drug substance. |
|
| 9 | Water content |
The test is Important for the drug substances which are known to be hygroscopic or degraded by moisture or when the drug substance is known to be a stoichiometric hydrate. In some cases, a Loss on Drying procedure may be considered adequate; however, a detection procedure that is specific for water (e.g., Karl Fischer titration) is preferred |
|
| 10 | Inorganic impurities |
The need for inclusion of tests and acceptance criteria for inorganic impurities (e.g., catalysts) shall be based on developmental studies. Procedures and acceptance criteria for sulfated ash / residue on ignition should be in line with pharmacopeial requirements. Other inorganic impurities may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy |
|
| 11 | Additional tests | Tests for chiral new drug substances |
Optically active drug substances may need specific identification testing |
What are various types of tests to be included in Finished Goods/ Drug Product specifications?
The specifications shall include following universal and product specific tests. Additional tests as deemed fit may also be included.
| S. No. | Type of Test | Test | Remarks |
| 1 | Universal Tests | Description |
Qualitative statement of the dosage form viz. (e.g., size, shape and color). |
| 2 | Identification | Identification testing should establish the identity of the new drug substance(s) in the new drug product. It should be able to discriminate between compounds
of closely related structure which are likely to be present. Identity tests should be specific for the new drug substance, e.g., infrared spectroscopy. |
|
| 3 | Assay |
A specific, stability-indicating procedure should be included to determine the content of drug product. In many cases, it is possible to employ the same procedure (e.g., HPLC) for both assay of the drug substance and quantitation of impurities. |
|
| 4 | Impurities |
Test (s) for Organic and inorganic impurities and residual solvents |
|
| 5 | Specific tests
(Tablets/ Capsules) |
Dissolution | The specification for solid oral dosage forms shall include a test to measure release of drug substance from the drug product. |
| 6 | Specific tests
(Tablets/ Capsules) |
Disintegration |
Disintegration testing is most appropriate when a relationship to dissolution has been established or when disintegration is shown to be more discriminating than dissolution. In such cases dissolution testing may not be necessary. Product development information shall be used to support the robustness of the formulation and manufacturing process with respect to the selection of dissolution vs. disintegration testing. |
| 7 | Specific tests
(Tablets/ Capsules) |
Hardness/friability |
Normally hardness and/or friability testing is performed as an in-process control. Hence, these shall be included in specifications only if they have a critical impact on drug product quality. |
| 8 | Specific tests
(Tablets/ Capsules/ Oral Liquids/ Parenteral) |
Uniformity of dosage unit | This term includes both the mass of the dosage form and the content of the active substance in the dosage form. In general, the specification should include one or the other but not both. |
| 9 | Specific tests
(Tablets/ Capsules) |
Water content |
A test for water content should be included when appropriate. The acceptance criteria may be justified with data on the effects of hydration or water absorption on the drug product. In some cases, a Loss on Drying procedure may be considered adequate; however, a detection procedure which is specific for water (e.g., Karl Fischer titration) is preferred |
| 10 | Specific tests
(Tablets/ Capsules/ Oral Liquids) |
Microbial limits |
Tests for the total count of aerobic microorganisms, the total count of yeasts and molds, and the absence of specific objectionable bacteria should be conducted except when its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination. |
| 11 | Specific tests
(Oral Liquids/ Parenteral) |
pH |
Acceptance criteria for pH should be provided where applicable and the proposed range justified |
| 12 | Specific tests
(Oral Liquids/ Parenterals) |
Antimicrobial preservative content |
For products requiring an antimicrobial preservative, acceptance criteria for preservative content should be established. Acceptance criteria for preservative content should be based upon the levels of antimicrobial preservative necessary to maintain microbiological quality of the product at all stages throughout its proposed usage and shelf-life. |
| 13 | Specific tests
(Oral Liquids/ Parenterals) |
Antioxidant preservative content | Release testing for antioxidant content should be performed. |
| 14 | Specific tests
(Oral Liquids/ Parenterals) |
Extractables |
Inclusion of test for extractables in specifications shall be based on product development and stability data. In case, this data shows that extractables concentration from container/ closure is consistently below certain level, then such test could be excluded, otherwise the test for extractables shall be included in the specifications. The need of this test shall be reassessed if the container/ closure system or formulation changes. Control of extractables from container/closure systems is considered significantly more important for parenteral products than for oral liquids. |
| 15 | Specific tests
(Oral Liquids) |
Alcohol content |
The same shall be included in specification if the content of alcohol is declared on label in accordance with pertinent regulations. |
| 16 | Specific tests
(Oral Liquids) |
Dissolution |
To include dissolution testing and acceptance criteria for oral suspensions and dry powder products for resuspension. The dissolution testing shall be performed at release. |
| 17 | Specific tests
(Oral Liquids/ Parenterals) |
Particle Size Distribution |
Quantitative acceptance criteria and a procedure for determination of particle size distribution shall be done for oral suspensions and injectable suspensions. The particle size distribution testing shall be performed at release. |
| 18 | Specific tests
(Oral Liquids/ Parenterals) |
Redispersibility |
For oral suspensions and injectable suspensions which settle on storage (produce sediment), the test for redispersibility shall be included. |
| 19 | Specific tests
(Oral Liquids) |
Rheological Properties | To include test for rheological properties for relatively viscous solutions or suspensions |
| 20 | Specific tests
(Oral Liquids) |
Reconstitution Properties |
Test for reconstitution time shall be provided for oral dry powder and parenteral products requiring reconstitution. Based on product develop data decision of eliminating or performing skip lot testing may be taken. |
| 21 | Specific tests
(Oral Liquids) |
Water content |
Test for water content may be included for dry powder products requiring reconstitution. |
| 22 | Specific tests
(Parenteral) |
Sterility | All parenteral products should have a test procedure and acceptance criterion for evaluation of sterility. Where data generated during development and validation justify parametric release, this approach may be proposed for terminally sterilized drug products. |
| 23 | Specific tests
(Parenteral) |
Endotoxin/ Pyrogens |
To test the presence of endotoxin LAL test shall be included. Pyrogenicity testing may be proposed as an alternative to endotoxin testing where justified. |
| 24 | Specific tests
(Parenteral) |
Particulate Matter |
To test the presence of visible particulates and / or clarity of solution, as well as for sub-visible particulates. |
| 25 | Specific tests
(Parenteral) |
Water content | Test for water content may be included for non-aqueous parenterals. |
| 26 | Specific tests
(Parenteral) |
Functionality testing of delivery systems |
The tests may include control of syringeability, pressure, and seal integrity (leakage), and/or parameters such as tip cap removal force, piston release force, piston travel force, and power injector function force. |
| 27 | Specific tests
(Parenteral) |
Osmolarity |
The tests for osmolarity shall be included where tonicity of product is declared on the label. |
What are release and shelf-life specifications? How are these different from each other?
Shelf-life specifications are normally the pharmacopeial or the in-house specifications approved by regulatory authority, which the product shall be meeting during its entire shelf-life.
Release specifications are the In-house specifications established by drug product manufacturer. These specifications are often tighter than the pharmacopeial or the in-house specifications approved by regulatory authority. These tighter specifications help the manufacturer to ascertain that the drug product shall continue to meet the specifications throughout its shelf life.
The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only. This may be applicable to parameters such as assay and impurity (degradation product) levels.
In European Union there is a regulatory requirement for distinct specifications for release and for shelf-life where ever they are different. In Japan and the United States, this concept may only be applicable to in-house criteria, and not to the regulatory release criteria. Thus, in these regions, the regulatory acceptance criteria are the same from release throughout shelf-life. However, the manufacturer may choose to have tighter in-house limits at the time of release.
Can we perform tests enlisted in a specification on batch to batch basis? What is periodic or skip testing?
A firm may decide which are the tests that are to be performed on each batch and which tests are to be performed periodically on batch to batch basis or can be skipped from regular testing. Periodic or skip testing is the performance of specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. This reduced testing shall be justified and presented to and approved by the regulatory authority prior to implementation.
This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms. When tested, any failure to meet acceptance criteria established for the periodic test should be handled by proper notification of the appropriate regulatory authority(ies). If these data demonstrate a need to restore routine testing, then batch by batch release testing should be reinstated.
Can we revise the specifications?
Definitely, as the manufacturer gains experience with the manufacture of the formulation, and the test methodology, changes in the specifications may be necessary to ensure that the methods are robust and are capable of producing consistent and reliable analytical results. Changes in the product or its manufacturing process may further impact analytical testing.
Changes / revisions in pharmacopeia may also lead to change in specifications. However, such changes, shall be assessed for their impact on the drug product.
Any changes in specifications shall be routed through change control procedure and appropriate regulatory approval shall be sought before implementing the revised specifications.
Do we require specifications for excipients, intermediates and packaging components?
Absolutely, any substance/component to be used for manufacturing and packaging of a formulation shall meet pre-defined specifications before they are used for a formulation.
Excipients: In most of the cases, the pharmacopeia provides clear specifications for the excipients. So, it is always helpful for the companies to use pharmacopeial excipients. For the product specific requirements, a firm may include additional tests in the specifications like flow, viscosity, particle size distribution etc. For this, the firm shall have thorough knowledge about the manufacturing process.
Intermediates: Specification for intermediates are necessary to ensure that the material is for use for further processing.
Packaging Components: A firm shall develop the specifications for the quality control. Product contact materials like Primary Packaging Material are critical, hence, thorough evaluation shall be put in place before finalizing its specifications.
