1. Purpose
The purpose of this guideline is to describe the process for generation, approval and management within R&D of specifications for release of materials used in clinical trials during drug development. It also gives guidance on the contents of such specifications for drug substance, several common types of investigational medicinal products and excipients.
2. Scope and Applicability
The guideline covers Specifications for non-complex bulk drug substances (APIs)and investigational medicinal products for clinical trials and is also intended for specifications for excipients during the development phase. Specifications for primary packaging material and container closure system are covered in another manual.
3. Definitions
3.1 Active Pharmaceutical Ingredient (API)
Any substance or mixture of substances intended to be used in the manufacture of drug medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.
3.2 Analytical Procedures
The method of analysis that is unequivocally related to a certain specification document is called “the analytical procedure” in this guideline. It may be the analytical procedure for each individual specification requirement or it may be one document containing all procedures needed to demonstrate compliance to the specification. It may be the regulatory version or a more detailed internal (local)version of the procedure depending on phase of development.
3.3 Internal Specification/Specification
For the purpose of this guideline the word specification means the specifications used for formal release within R&D. Thus, for sites using internal specifications or provisional specifications those are the specifications covered.
If internal specifications are not used the regulatory specification and the release specification will be the same.
An internal specification may be used to cover all requirements included in the different regulatory specifications submitted to different authorities, without having to update all different regulatory specifications when new requirements need to be included for a certain region or country. For the purpose of compliance and formal release of materials in clinical studies (covering all relevant countries) the appropriately updated internal specification is used.
The internal specification is a release specification and limits may not necessarily cover end of shelf-life requirements. Those are covered in the regulatory specification and may also be included for information in the internal specification.
An internal specification may also include tests for the purpose of collecting additional data for the possible inclusion/exclusion in a later version of regulatory specification. In such cases the specification limit(s) may be substituted by “for information”.
Specifications/Internal specifications must be subject to change and version Control.
3.4 Investigational Medicinal Product (IMP)
A pharmaceutical form of an active substance or placebo being tested or used as reference in a clinical trial, including products already with a marketing authorization when used or manipulated (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about the authorized form.
3.5 Genotoxic Impurity
An impurity for which there is experimental evidence for genotoxic activity from relevant validated test.
3.6 Potential Genotoxic Impurity
Any impurity where there is believed to be cause to believe it likely to be genotoxic. This is most likely to result from either comparison with Destructor alerts or through a SAR evaluation process.
3.7 Product Specification File (PSF)
A PSF is a reference file containing, or referring to files containing all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product.
3.8 Regulatory Specification
A regulatory specification (file specification) is the specification included in the submission to regulatory authorities (IND, CTA, MAA/NDA) and that subsequently will be/has been approved by a health authority and includes the tests, acceptance criteria and analytical methodology.
4. Responsibilities
Specifications for API shall be jointly approved by line management withered Analytical Chemistry (AC), R&D Early Development (ED) or Analytical Development (AD), and by R&D QA.
Specifications for Drug product and Drug product intermediate as well as excipients shall be approved by R&D Early Development (ED) or Analytical Development (AD) line management and R&D QA. Packaging material specifications are approved by Product Development (PD) and R&D QA.
4.1 Author
The author for the release specification is responsible:
*For writing the specification document in a timely manner so that it is ready (and valid) before release of material for clinical studies. Generic specifications following the requirements for phase 1 (outlined in Appendix 1) may be used at early stages of development. At early development stages analysis may have been performed prior to the existence of a valid release specification, e.g. Campaign 2 drug substance.
* For consulting with the relevant people within project teams or sub-teams as appropriate (e.g. ED, AD, PD, R&D, CMC Documentation, QA) and/or line functions according to local routines.
* For the detailed contents of the specification. Standard requirements for anapsid/IMP or excipient are given in Appendices 1 and 2.
* That, if the specification does not follow the standard requirements, e.g. Those given in the Appendices, this should be justified/documented, e.g. informally approved meeting minutes, a formal internal document “justification of specification” or an appropriate history log.
A specific “function”/person (which could be the author) at the R&D site should be responsible for initiating, indexing and finalizing the specification document and distributing it according to local procedures.
4.2 Line management
The line managers within R&D Analytical Chemistry and R&D Early Development or Analytical Development (depending on the stage of development) (function or team managers or appointed person with special delegation), are jointly responsible for approving the API specification together with R&D QA.
The line manager within R&D Early Development or Analytical Development (function or team manager or appointed person with special delegation), is responsible for approving the pacification for either the Drug product and Drug product intermediate as well as excipients together with R&D QA.
In both cases the approval shall ensure,
* That the specification is prepared as described in this guideline
* That the tests and requirements are fit for purpose (technically/scientifically, phase, regulatory and pharmacopoeia requirements and use) and do not unnecessarily deviate from other similar products/substances and where applicable, appropriate justifications will be in place.
* That any changes to specifications are controlled and that GMP and regulatory change control processes are initiated when required.
* That the specification is in line with (i.e. covers the requirements in) the regulatory specifications valid at the time of issuing.
* That analytical procedures that are fit for purpose and validated as required by the phase are available
* That input from stakeholders has been appropriately taken into account.
4.3 QA
QA is responsible for approving the specification, which means:
* Ensure that an approved specification is in place
* Ensure that documented decisions/justifications of deviations from the guidance given in Appendix 1 and 2 will be available
* Ensure that analytical procedure (s) and validation as required by stage of development exist
* Ensure that the specification can be used for batch release
5. Guideline
A specification should be issued prior to quality control and release of the material. (N.B. At early development stages analysis may have been performed prior to the existence of a valid release specification, e.g. Campaign 2 drug substance. Generic specifications following the requirements for phase 1(outlined in Appendix 1) may be used at this stage of development).
The individual(s) (i.e. the author and an administrator, if different from author) responsible for the preparation of the specification for a drug substance, drug product, drug product intermediate or excipient will:
* Consult with R&D and/or sub-team members and with approving line managers within ED, AD, PD and/or R&D and QA, as appropriate.
* Ensure that sufficient “justification” documentation will be in place if specification requirements are outside standards given in Appendix 1
for drug substance and drug product or in Appendix 2 for an excipient.
This justification should be approved by manufacturing (ED, PD ordo) and approving line functions.
* Ensure that the specification is approved by line management and QA
* Make specification “approved “in documentation system if signed in wet ink
* Inform users/stakeholders that the approved, dated and valid specification is available
6. Appendices
6.1 Appendix 1
6.1.1 Contents of Specifications for the release of Non-Complex Active Pharmaceutical Ingredients and Drug products for clinical studies
In this Appendix the word specification is used for the specification used for release of materials for clinical trials. Also included are standard quality requirements of material intended for toxicological studies (GLP-studies). The analytical testing of a new drug substance or drug product should normally not be restricted to that formally required by the specification.
Collection of additional data to support the ultimate NDA/MAA/JNDA specifications (and the analytical methods supporting those) can/should be made in parallel to the formal release testing. Such items may be included as “For information” in the specification. If a “for information” clause is included in regulatory specification it should be accompanied by an explanatory footnote egg.
“a review will be made for the need of this specification clause and if required acceptance criteria will be established at a later phase of development’’.
Specifications during development must be subject to change control
The name of the API or Dosage Form should be clearly stated in the heading of the specification. Specifications used during development should follow the general format of NDA/MAA specifications.
The following Specifications/Tests should be included in all specifications for Drug Substance and Drug Product:
* Description (may be omitted as requirement for drug substance for Phase I and I if Appearance of solution is included)
* Identification: typically, by IR or NMR for the API and minimally by chromatographic retention measure for the drug product; include a chiral identity and a counter-ion identity as appropriate
* Assay (non-chiral is acceptable); normally 90-110% at release and end of shelf life for stable oral and parenteral dosage forms. If significant degradation takes place in a drug product during shelf life a tighter specification limit at release should be considered.
6.1.2 Bulk Drug Substance (API)
In addition to Description, Identification and Assay the following specification tests marked x should be included or their absence justified.
Specification tests marked (x) should be considered (inclusion or not depending on drug substance properties and intended dosage form).
6.1.2.1 Microbiological limits
For substances intended for parenteral use selected requirements for Bioburden/Microbiological limits Endotoxins/Sterility should be included as appropriate (limits as for MAA/NDA). For substances intended for the oral route limit of not more than 103 (102 for Sweden) microorganisms (CFU)/g may be appropriate, if included. (Micro testing is a mandatory requirement in some countries)
6.1.2.2 Organic Impurities
Organic impurities should normally be expressed as per cent of the active moiety, not of the salt form. Percentages within brackets in the table above indicate that flexibility should be considered.
* If possible, impurities above 0.5% in batches for toxicological studies should be sufficiently identified to allow for an assessment of risk /benefit of relevance to the toxicology study, especially for mutagenicity tests.
** For a related impurity (e.g. similar UV-spectrum) a limit corresponding to the qualification thresholds for degradants in drug products in the ICH guideline on Impurities in New Drug Products (Q3B(R)) may be applied, normally 0.2%.
If the same batch was previously used in relevant tax studies the limits given Ove for Tux may be applied also for Phase I/II
*** For inclusion of a specification limit for Phase III material for a “toxicologically unqualified” impurity higher than 0.1% the Toxicology Project Leader should be consulted. For a specified impurity present in relevant tax studies (1 month and longer) a specification limit higher than the level in the batch used in theta studies can sometimes be applied.
“Single impurity” is used for a specified and qualified impurity that may or may not have been identified (ICH nomenclature) in the table above for Phase I – III.
“Unknown impurity” is used for an unqualified and unspecified impurity that may or may not have been identified.
**** These limits may vary depending on type of impurity, e.g. potential genotoxic impurities (PGI). An assessment of PGI should be conducted in accordance with the company’s Internal Guideline for the risk assessment of potential genotoxic impurities in development compounds (in draft when this guideline was issued).
For those impurities for which there are structural alerts and/or safety data indicate genotoxicity (e.g. positive AMES test) appropriate control must be exercised, either by specification limits or by other procedures, e.g. documented in genotoxic strategy document.
Limits will depend upon several factors including, among others, the clinical phase (duration of treatment) and the therapy area. Limits should be set in line with the guidance provided in the internal guideline and due to the complex nature of how such limits are derived should be agreed jointly between relevant functions within the GPT. An example of permissible limits is given in Table 1.
In order to determine the permissible level in concentration terms in the API the likely daily dose needs to be established.
Tests for PGI impurities must be clearly identified within the specification and the results from these analyses must be part of the formal release process.
For PGIs results should normally be expressed in terms of parts per million.
6.1.2.3 Chiral Impurities
A default limit of not more than 2% of the unwanted enantiomer (or a specified diatreme) may be applied, at least during Phase I/II. For qualification the ICH thresholds for qualification for New Drug Products may be followed.
6.1.2.4 Catalysts and other heavy metals
A 20 ppm (w/w) limit for Sn, Ni, Pad, Pt, Pub, Co, Ag, V, Mo and Cu may be applied in early development, if applicable, for substances intended for oral administration. A 10 ppm limit (or possibly lower, egg for palinodes) is recommended from phase III.
Limits for other metal residues should be discussed with the project member.
For substances intended for, e.g. parenteral administration and/or for materials with high daily doses lower limits may be appropriate.
6.1.2.5 Residual solvents
The solvents used in the last step(s) of the synthesis should be specified with appropriate limits (see Q3C and Q3CM). If only class three solvents are used in the synthetic route an LOD-limit of NMT 0.5% may be used.
Alternatively, the specification requirement could be phrased as” Fulfils the ICH requirements for residual solvents”.
Solvents not covered by Q3C and used in the last step(s) of the synthesis should be specified with individual limits (limits should be discussed with Safety Assessment). For any solvent present at above 0.5% (w/w) a specified limit should be included.
6.1.2.6 Assay
The lower limit may depend on the limit for organic impurities and if correction for residual solvents/water is made or not.
Tighter limits could be applied if a more precise, though non-specific, titrimetric method is used for the assay. Percentages within brackets in the table above indicate that flexibility should be considered.
6.1.2 Tablets and Capsules (immediate release (IR) and extended release (ER)), Oral powders and granules, Oral solutions and suspensions (unit dose)
In addition to Description, Identity and Assay the following specification tests should be included (examples of wording given below):
6.1.4 Placebo (for tablets etc.)
6.1.5 Parenteral solution (Single Dose Containers)
Limits for “Deliverable” volume, Tonicity and Colour should be considered but should, if possible, be kept out of the regulatory specification prior to the start of stability studies for NDA/MAA. In order to collect data these tests may be included in the specification “for information” When included in the specification “Degradation products” should be worded similarly to” Organic impurities” for the API.
6.1.6 Placebo (for parenteral solution)
6.1.7 Other Dosage forms
R&D at the site for development or if applicable, the Centre of Excellence for the specific dosage form should establish/provide guidance for the appropriate specification requirements.
6.2 Appendix 2
Contents of Specifications for Excipients during development
6.2.1 Pharmacopoeia excipients
In regulatory files reference is given to that the excipient fulfils pharmacopoeia requirements (Ph. Ear, USP/NF or JP/JPE). No regulatory specification is included in the file.
A specification is needed for release purpose only. Alternatively, the excipient may be released against the relevant pharmacopoeia monograph.
For phase 1 and 2, requirements of only one pharmacopoeia has to be fulfilled. For phase 3, it is recommended that the release specification fulfil the requirements of that pharmacopoeia, which is legal in the region where the clinical studies are performed (USP/NF in US; Ph. Ear in Europe; JP/JPE in Japan), although this is not an absolute requirement.
6.2.1.1 Content of specification Provided
* The manufacturer is an established excipient manufacturer or otherwise well known, e.g. currently supplying other excipients.
* Good knowledge about the excipient/ (class of excipient), e.g. similar excipients have previously been approved and used.
* The excipient will be used in early phase studies (phase I/II). the analytical results can be taken from the manufacturer’s CoA without prior assessment and approval of the manufacturer for the specific excipient. This decision should be documented appropriately.
The specification should clearly show, which results that are to be taken from the manufacturer’ s CoA and the requirements for those test points. Alternatively, the requirement in the in-house specification can be that a CoA from the manufacturer is available that shows compliance to the relevant pharmacopoeia, e.g. Ph. Eur.
As a minimum, identification should always be performed by the receiving company. Also description is recommended, as well as microbiological testing (not more than102CFU/g is a mandatory requirement in some countries).
6.2.2 Non-pharmacopoeia excipients
A specification for a novel non-pharmacopoeia excipient should normally include the same requirements as those for an API. For a non novel excipient an existing pharmacopoeia monograph for the same class of excipient should be used as a “template”, if possible.
Any new excipients must be assessed in terms of their potential genotoxicity.
6.2.3 Additional information
In addition to compliance to the requirements of a specific pharmacopoeia monograph, the excipient supplier should be asked to give certain additional information.
* TSE statement:
It is advisable to avoid excipients of animal origin.
* Origin of the excipient:
It may be necessary to know the origin of excipients, since some patients must avoid certain excipients for allergic or religious reasons.
* Residual solvents:
The ICH guideline regarding residual solvents should be fulfilled. If the excipient contains a Class 2 solvent above the Option 1 limit the amount should be reported on the analytical certificate.
* Route of Manufacture