The Quality Assurance Function and the Qualified Person (QP)
Product Specification File
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In the EU, an individual Qualified Person must certify the GMP compliance for each batch of drug product, both commercial
or investigational. The responsibilities of the Qualified Person are provided in Annex 1612 to the EU GMPs. For IMPs, the Qualified Person must also certify that the executed batch records are in concert with the
Product Specification File, explained in Annex 13, chapter 9 (see the sidebar) and with the Quality (CMC) section of the IMP
Dossier. If IMPs are manufactured or packaged in the US and then imported into the EU, the EU qualified person certification
is usually given only after a compliance audit, which is conducted according to EU GMP and Annex 13 standards.
In the US, the Quality Assurance function is responsible for conducting a production record review according to 211.192 and
for ensuring CMC contractors meet GMPs (211.22 a). These basic requirements are the same for commercial and investigational
drug products.
In the EU, there is a formal 2-step release process for IMPs (see Annex 13, article 44, and the CTD, 2001/20/EC, article 9).
The GMP release involves the certification of the qualified person as described above. The GCP release involves assurances
that the CTA has been submitted and a favorable opinion received from the Competent Authorities and the Ethics Committee (in
the US, this committee is called an Institutional Review Board, or IRB). In the US, the release process is not codified. It
is common for the GCP "regulatory" release to include receipt and review of documents including FDA Forms 1571 and 1572, the
investigator's curriculum vitae, indemnification forms, IND submission and 30 day wait and IRB approval. The GMP release is usually based on a batch record
review and evaluation of Certificate of Analyses.
Amendments to the EU CTA and the US IND
The European CTA is, on the surface, extremely similar to the US IND. Both involve submission of basic CMC, toxicology, and
clinical program information to the appropriate regulatory bodies for review. The depth and extent of the details required
are readily available.
In the US, the FDA Guideline on CMC requirements for Phase 1, Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-derived Products
13 briefly describes the CMC information required. In the EU, the websites for the UK's Medicines and Healthcare products Regulatory
Agency (MHRA) and the French regulatory authorities contain similar descriptions and excellent examples of the depth of information
required; with few exceptions, these requirements are similar to those in the US.14, 15 The review timeframe is similar (30 days in the US, 60 days in the EU) although, in practice, many of the competent authorities
have consistently completed their reviews in under 35 days.
During early drug development, frequent changes are made to every aspect of CMC development: formulation, ingredients, quantitative
amounts, various strengths of the investigational drug products, method of manufacture, scale and batch size, analytical methods,
specifications, packaging and labeling. Updates to the IND and CTA are handled by amendments, but there is a substantial difference
between the two regions in the way these updates are handled.
In the US, changes to original IND submissions that have safety implications (e.g., a new synthesis route or if large-scale
API synthesis produces new or higher levels of impurities than those previously used in toxicology studies) are best handled
by amendments followed by verbal or written confirmation that the changes are acceptable. Other updates to the IND may be
made without prior approval in an annual report or an information amendment such as the Post Approval Changes Being Effected
(CBE) process.
In the EU, updates are made through amendments, which can be classified as major or minor. In the post-2004 CTA era, all major
amendments require prior approval from the competent authorities, yet even in 2006, there is a lack of agreement among the
25 member states about what constitutes a major amendment. For example, in the UK, the MHRA expects to formally review and approve the original and any extensions to the
provisional or tentative expiry (or shelf life or retest) date, and has requested the actual stability data that were used
by the sponsor to project the expiry date.
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